Novel anilide compounds and drugs containing the same

ABSTRACT

The invention relates to a novel anilide compound and a pharmaceutical composition comprising the same. The invention relates to a compound represented by the following general formula:  
                 
 
     represents a divalent residue of benzene with a substituent(s), heterocycle-condensed benzene which may or may not have a substituent, pyridine which may or may not have a substituent, cyclohexane or naphthalene  
                 
 
     Ar represents an aryl group which may or may not have a substituent,  
     X represents —NH—, oxygen atom or sulfur atom;  
     Y represents —NR 4 —, oxygen atom, sulfur atom, sulfoxide or sulfone;  
     Z represents single bond or —NR 5 —;  
     R 4  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent;  
     R 5  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent; and  
     n represents an integer of 0 to 15.  
     The inventive compounds are useful in the form of pharmaceutical composition, specifically as acyl coenzyme A cholesterol acyltransferase (ACAT) inhibitor.

TECHNICAL FIELD

[0001] The present invention relates to a novel anilide compound and apharmaceutical composition containing the same. More specifically, theinvention relates to a compound represented by the general formula I:

[0002] represents a divalent residue of benzene with a substituent(s),heterocycle-condensed benzene which may or may not have a substituent,pyridine which may or may not have a substituent, cyclohexane ornaphthalene

[0003] Ar represents an aryl group which may or may not have asubstituent;

[0004] X represents —NH—, oxygen atom or sulfur atom;

[0005] Y represents —NR₄—, oxygen atom, sulfur atom, sulfoxide orsulfone;

[0006] Z represents single bond or —NR₅—;

[0007] R₄ represents hydrogen atom, a lower alkyl group, an aryl groupor a silylated lower alkyl group which may or may not have asubstituent;

[0008] R₅ represents hydrogen atom, a lower alkyl group, an aryl groupor a silylated lower alkyl group which may or may not have asubstituent; and

[0009] n represents an integer of 0 to 15;

[0010] a salt thereof or a solvated compound thereof and pharmaceuticalcompositions comprising these compounds.

BACKGROUND OF THE INVENTION

[0011] Following the transfer of the (Japanese) dietary life toEuropean-style diets comprising high calorie and high cholesterol due tothe improvement of the living standard and the increase of the ratio ofaged people in the (Japanese) population, hyperlipidemia andarteriosclerotic diseases caused by hyperlipidemia have increased innumber rapidly in recent years. The increase of these diseases is nowone of the social problems (in Japan). Conventional pharmaceuticaltreatment of hyperlipidemia and arteriosclerosis has mainly targeted thereduction of lipid in blood as the etiology thereof. The treatment hasnever targeted arteriosclerotic lesions of themselves. Acyl coenzyme Acholesterol acyltransferase (ACAT) is the enzyme to catalyze thesynthesis of cholesterol ester from cholesterol to play a significantrole in the cholesterol metabolism and absorption in gastrointestinaltract. It is suggested that the inhibition of ACAT esterifying freecholesterol in the epidermal cell of small intestine works to inhibitcholesterol absorption from intestinal lumen and that the inhibition ofcholesterol ester generation in liver owing to ACAT inhibitionsuppresses VLDL secretion from liver into blood stream, with theresultant action to decrease blood cholesterol. It is considered thatmany of conventional ACAT inhibitors function as anti-lipidemia agentsto exert the action of decreasing blood cholesterol by allowing theinhibitors to react with the ACAT enzyme in small intestine and liver.

[0012] As ACAT inhibitors, for example, U.S. Pat. No. 4,716,175describes 2,2 dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide; and EP372, 445 describesN′-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptylurea in the specification. However, many of these conventional ACATinhibitors as anti-hyperlipidemia agents principally work to decreaseblood cholesterol and are administered at large doses to permitsufficient exertion of the action. Due to the emergence of side effectsincluding intestinal bleeding, intestinal disorders, diarrhea and liverdisorders at high frequencies at clinical test stages, accordingly, thedevelopment of these agents for clinical practice has been verydifficult.

[0013] Arteriosclerosis is a disease essentially involving uniquefeatures of hypertrophy of inner vascular membrane and lipidaccumulation. Recent research works indicate that suppression ofmacrophage foaming essentially functioning for the formation ofarteriosclerotic lesions possibly degenerates arteriosclerotic lesions.Macrophage-derived foam cell (storing cholesterol ester as lipid dropletinside the cell) is observed in arteriosclerotic lesions. It isindicated that macrophage foaming is deeply involved in the progress ofthe disease. Additionally, it is reported that ACAT activity is elevatedin the wall of blood tubes in arteriosclerotic lesions, indicating thatcholesterol ester is accumulated in the wall of blood tubes (Gyres, P.J. et al., Exp. Mole. Pathol., 44, 329-339 (1986)).

[0014] Due to the inhibition of cholesterol esterification by ACATinhibitors, free cholesterol is generated inside cells and is theneliminated with high-density lipoprotein (HDL) to be transferred to andmetabolized in liver (reverse transfer by HDL). It is suggested that theaccumulation of cholesterol in diseased sites is thereby suppressed.Consequently, direct anti-arteriosclerotic action is exerted. A reporttells that ACAT includes two sub-types, namely an ACAT type present insmall intestine and an ACAT type, present in vascular wall (Quinoonen,P. M. et al., Biochem., 27, 7344-7350 (1988)). Conventional researchworks on ACAT inhibitors have mostly been carried out by using the ACATtype present in small intestine and liver (Tomoda, H. et al., J.Antibiotics 47, 148-153 (1994)). Based on the assumption that apharmaceutical agent selectively inhibiting the ACAT type which presentsin vascular wall may work as a therapeutic agent of arteriosclerosiswith less side effects, the present inventors have syntheticallyproduced such inhibitors and have carried out examinations on them.

DISCLOSURE OF THE INVENTION

[0015] So as to attain the object, the inventors have madeinvestigations. Consequently, the inventors have found that a compoundrepresented by the general formula I:

[0016] represents a divalent residue of benzene with a substituent(s),heterocycle-condensed benzene which may or may not have a substituent,pyridine which may or may not have a substituent, cyclohexane ornaphthalene

[0017] Ar represents an aryl group which may or may not have asubstituent;

[0018] X represents —NH—, oxygen atom or sulfur atom;

[0019] Y represents —NR₄—, oxygen atom, sulfur atom, sulfoxide orsulfone;

[0020] Z represents single bond or —NR₅—;

[0021] R₄ represents hydrogen atom, a lower alkyl group, an aryl groupor a silylated lower alkyl group which may or may not have asubstituent;

[0022] R₅ represents hydrogen atom, a lower alkyl group, an aryl groupor a silylated lower alkyl group which may or may not have asubstituent; and

[0023] n represents an integer of 0 to 15;

[0024] a salt thereof or a solvated compound thereof exerts an excellentACAT inhibitory action. Thus, the invention has been achieved.

[0025] The inventors have found that the inventive compounds exert ACATinhibitory actions in an organ-specific manner and an action inhibitingthe transfer of intra-cellular cholesterol and that the inventivecompounds are particularly useful as anti-hyperlipidemia agents with anexcellent action to reduce cholesterol in blood and as a prophylacticand therapeutic agent of arteriosclerosis with an action to suppressmacrophage foaming.

[0026] Thus, the compound represented by the general formula I, a saltthereof or a solvated product thereof is provided in accordance with theinvention.

[0027] Additionally, the invention provides pharmaceutical compositionscomprising the compound represented by the general formula I, a saltthereof or a solvated product thereof, together with carrierspharmaceutically acceptable.

[0028] Still additionally, the invention provides the compounds shown asthe above formula I, salts thereof or solvated compounds thereof, andACAT inhibitors, agents inhibiting intra-cellular cholesterol transfer,blood cholesterol-reducing agents, or macrophage foaming-suppressingagents. In other words, the invention provides therapeutic andprophylactic agents of diseases including hyperlipidemia,arteriosclerosis, arteriosclerosis of carotid and cerebral arteries,cerebrovascular diseases, ischemic cardiac diseases, coronaryarteriosclerosis, nephrosclerosis, arteriosclerotic nephrosclerosis,arteriocapillary sclerotic nephrosclerosis, malignant nephrosclerosis,ischemic intestinal diseases, acute mesenteric blood tube occlusion,chronic intestinal angina, ischemic colitis, aortic aneurysm andocclusive arteriosclerosis (ASO).

[0029] As compounds similar to the compound of the formula I,3-(benzothiazol-2-ylthio)-N-(phenyl)propanamide and3-(benzoxazol-2-ylthio)-N-(phenyl)propanamide are disclosed in J. Chem.Eng. Data, 27, 207 (1982) and Fungitsidy, Ed. Melnilov, N. N. Izd. FanUzb. SSR: Tashkent, USSR. 82-88 (1980), respectively. However, it hasabsolutely never been known that these compounds exert ACAT inhibitoryactions.

BEST MODE FOR CARRYING OUT THE INVENTION

[0030] Preferable examples of the compound represented by the generalformula I in accordance with the invention include a compoundrepresented by the following formula II, a salt thereof or a solvatedproduct thereof, and a compound represented by the following formulaIII, a salt thereof or a solvated product thereof:

[0031] represents a divalent residue of benzene with a substituent(s),heterocycle-condensed benzene which may or may not have a substituent,pyridine which may or may not have a substituent, cyclohexane ornaphthalene

[0032] X represents —NH—, oxygen atom or sulfur atom;

[0033] Y represents —NR₄—, oxygen atom, sulfur atom, sulfoxide orsulfone;

[0034] Z represents single bond or —NR₅—,

[0035] R₁, R₂ and R₃ may be the same or different and represent hydrogenatom, a lower alkyl group, a lower alkoxyl group, halogen atom, hydroxylgroup, phosphate group, sulfonamide group, or amino group which may ormay not have a substituent; otherwise, any combination of two of R₁, R₂and R₃ represents an alkylene dioxy group;

[0036] R₄ represents hydrogen atom, a lower alkyl group, an aryl groupor a silylated lower alkyl group which may or may not have asubstituent;

[0037] R₅ represents hydrogen atom, a lower alkyl group, an aryl groupor a silylated lower alkyl group which may or may not have asubstituent; and

[0038] n represents an integer of 0 to 15;

[0039] wherein

[0040] X represents —NH—, oxygen atom or sulfur atom;

[0041] Y represents —NR₄—, oxygen atom, sulfur atom, sulfoxide orsulfone;

[0042] Z represents single bond or —NR₅—;

[0043] R₁, R₂ and R₃may be the same or different and represent hydrogenatom, a lower alkyl group, a lower alkoxyl group, halogen atom, hydroxylgroup, phosphate group, sulfonamide group, or amino group which may ormay not have a substituent; otherwise, any combination of two of R₁, R₂and R₃ represents alkylene dioxy group;

[0044] R₄ represents hydrogen atom, a lower alkyl group, an aryl groupor a silylated lower alkyl group which may or may not have asubstituent;

[0045] R₆, R₇ and R₈ may be the same or different and represent hydrogenatom, a lower alkyl group which may or may not have a substituent, alower alkoxyl group which may or may not have a substituent, halogenatom, hydroxyl group, carboxyl group, an alkoxycarbonyl group which mayor may not have a substituent, an alkylcarbonyloxy group which may ormay not have a substituent, an alkylcarbonyl group which may or may nothave a substituent, carbamoyl group which may or may not have asubstituent, a hydroxyalkyl group, phosphate group, cyano group, nitrogroup, sulfonamide group, amino group which may or may not have asubstituent, an aminoalkyl group which may or may not have asubstituent, or a heterocyclic residue; otherwise, any combination oftwo of R₆, R₇ and R₈ represents an alkylene dioxy group, provided thatR₆, R₇ and R₈ never simultaneously represent hydrogen atom; and

[0046] n represents an integer of 0 to 15. More preferable is a compoundrepresented by the following general formula IV, a salt thereof or asolvated product thereof:

[0047] X represents —NH—, oxygen atom or sulfur atom;

[0048] Y represents —NR₄—, oxygen atom, sulfur atom, sulfoxide orsulfone;

[0049] Z represents single bond or —NR₅—;

[0050] R₁, R₂ and R₃may be the same or different and represent hydrogenatom, a lower alkyl group, a lower alkoxyl group, halogen atom, hydroxylgroup, phosphate group, sulfonamide group, or amino group which may ormay not have a substituent; otherwise, any combination of two of R₁, R₂and R₃ represents an alkylene dioxy group;

[0051] R₄ represents hydrogen atom, a lower alkyl group, an aryl groupor a silylated lower alkyl group which may or may not have asubstituent;

[0052] R₅ represents hydrogen atom, a lower alkyl group, an aryl groupor a silylated lower alkyl group which may or may not have asubstituent;

[0053] R₉, R₁₀, R₉′, R₁₀′, R₉″, R₁₀″, R₉′″, and R₁₀′″ may be the same ordifferent and represent hydrogen atom, a lower alkyl group which may ormay not have a substituent, a lower alkoxyl group which may or may nothave a substituent, halogen atom, hydroxyl group, carboxyl group, analkoxycarbonyl group which may or may not have a substituent, analkylcarbonyloxy group which may or may not have a substituent, analkylcarbonyl group which may or may not have a substituent, carbamoylgroup which may or may not have a substituent, a hydroxyalkyl group,phosphate group, sulfonamide group, amino group which may or may nothave a substituent, an aminoalkyl group which may or may not have asubstituent, or a heterocyclic residue; otherwise, any combination oftwo thereof represents an alkylene dioxy group; and

[0054] n represents an integer of 0 to 15.

[0055] Ar in the general formula I represents an aryl group which may ormay not have a substituent; a specifically preferable group is thefollowing group:

[0056] wherein R₁, R₂ and R₃ may be the same or different and representhydrogen atom, a lower alkyl group, a lower alkoxyl group, halogen atom,hydroxyl group, phosphate group, sulfonamide group, or amino group whichmay or may not have a substituent; otherwise, any combination of two ofR₁, R₂ and R₃ represents an alkylene dioxy group.

[0057] The following group in the general formula I

[0058] represents a divalent residue of benzene with a substituent(s),heterocycle-condensed benzene which may or may not have a substituent,pyridine which may or may not have a substituent, cyclohexane ornaphthalene, or

[0059] A divalent residue of benzene with a substituent preferablyincludes the group represented by the following formula:

[0060] wherein R₆, R₇, and R₈ may be the same or different and representhydrogen atom, a lower alkyl group which may or may not have asubstituent, a lower alkoxyl group which may or may not have asubstituent, halogen atom, hydroxyl group, carboxyl group, analkoxycarbonyl group which may or may not have a substituent, analkylcarbonyloxy group which may or may not have a substituent, analkylcarbonyl group which may or may not have a substituent, carbamoylgroup which may or may not have a substituent, a hydroxyalkyl group,phosphate group, cyano group, nitro group, sulfonamide group, aminogroup which may or may not have a substituent, an aminoalkyl group whichmay or may not have a substituent, or a heterocyclic residue; otherwise,any combination of two of R₆, R₇, and R₈ represents alkylene dioxygroup, provided that R₆, R₇, and R₈ never simultaneously representhydrogen atom.

[0061] A divalent residue of heterocycle-condensed benzene which may ormay not have a substituent preferably includes the group represented bythe following formula:

[0062] wherein R₆ and R₇ may be the same or different and representthose described above; the ring B represents a saturated or unsaturatedheterocyclic group with at least one oxygen atom, nitrogen atom orsulfur atom in a 5- to 7-membered ring condensed with benzene ring.

[0063] A divalent residue of pyridine preferably includes the grouprepresented by the formula:

[0064] wherein R₉, R₁₀, R₉′, R₁₀′, R₉″, R₁₀″, R₉′″, and R₁₀′″ may be thesame or different and represent hydrogen atom, a lower alkyl group whichmay or may not have a substituent, a lower alkoxyl group which may ormay not have a substituent, halogen atom, hydroxyl group, carboxylgroup, an alkoxycarbonyl group which may or may not have a substituent,an alkylcarbonyloxy group which may or may not have a substituent, analkylcarbonyl group which may or may not have a substituent, carbamoylgroup which may or may not have a substituent, a hydroxyalkyl group,phosphate group, sulfonamide group, amino group which may or may nothave a substituent, an aminoalkyl group which may or may not have asubstituent, or a heterocyclic residue; otherwise, any combination oftwo thereof represents an alkylene dioxy group.

[0065] The aryl group in R₄ and R₅ is preferably phenyl group, naphthylgroup and the like; and these aryl groups may or may not have thesubstituents described above.

[0066] The lower alkyl group represented by each symbol in the generalformula I preferably includes a linear or branched alkyl group with oneto 15 carbon atoms, preferably one to 10 carbon atoms and morepreferably one to 6 carbon atoms. For example, the lower alkyl group ispreferably methyl group, ethyl group, n-propyl group, iso-propyl group,n-butyl group, iso-butyl group, tert-butyl group, n-pentyl group,n-hexyl group or the like. As the lower alkoxyl group, preference isgiven to an alkoxyl group comprising alkyl groups such as thosedescribed above. The alkoxycarbonyl group preferably contains thealkoxyl groups described above. The alkylcarbonyloxy group preferablycontains the lower alkyl groups described above. The alkylcarbonyl grouppreferably contains the lower alkyl groups described above.

[0067] Additionally, the lower alkyl groups, the lower alkoxyl groups,the alkoxycarbonyl groups, the alkylcarbonyloxy groups, thealkylcarbonyl groups or the carbamoyl groups may or may not havesubstituents. These substituents may work as alternative substituentsfor each other; for example, alkoxy lower alkyl group, alkoxyalkoxylgroup, lower alkoxyalkoxycarbonyl groups, alkoxycarbonyl-substitutedalkyl group, alkoxycarbonyl-substituted alkoxyl group,alkoxycarbonyl-substituted alkoxycarbonyl group may be possible.

[0068] Still additionally, other substituents include for examplehalogen atoms such as chlorine atom and fluorine atom, hydroxyl group,silyl groups such as trimethylsilyl group, dimethyl t-butylsilyl group,and dimethylphenylsilyl group, saturated or unsaturated heterocyclicresidues containing one or two or more oxygen atoms, nitrogen atoms orsulfur atoms in the ring thereof, such as oxethanyl group,tetrahydrofuryl group and pyrrolidinyl group. The alkylene dioxy grouppreferably contains a linear or branched alkylene group with one to 6carbon atoms.

[0069] The halogen atom is preferably fluorine atom, chlorine atom,bromine atom or iodine atom or the like. The amino group may or may notbe substituted with one or two substituents. The substituents for theamino group preferably include lower alkyl groups such as thosedescribed above, aryl groups such as phenyl group and naphthyl group,and aralkyl groups such as benzyl group and phenethyl group; and thearomatic rings thereof may or may not be substituted with lower alkylgroups and lower alkoxyl groups such as those described above,additionally. Furthermore, two of the substituents for the amino grouptogether may form a 5- to 7-membered ring which may or may not containoxygen, sulfur or nitrogen. The heterocyclic residues are preferably ofa monocycle, a polycycle or a condensed ring comprising a 5- to7-membered ring, saturated or unsaturated, containing one or twohetero-atoms, preferably one to four hetero-atoms such as oxygen atom,nitrogen atom or sulfur atom; and these heterocyclic residues may or maynot be substituted with the lower alkyl groups, the lower alkoxylgroups, the alkylene dioxy groups, halogen atom, the amino group, andsubstituted amino groups. The heterocyclic residues include for exampletetrazolyl group, 2-, 4- or 5-imidazolyl group, 3- or 4-pyrazolyl group,2-, 4- or 5-oxazolyl group, 2-, 4- or 5-thiazolyl group, oxazolin-2-, 4-or 5-yl group, [1,3]-dioxylan-2- or 4-yl group, and these heterocyclicresidues substituted with lower alkyl groups such as methyl group andethyl group.

[0070] The acid addition salt of the compound I in accordance with theinvention includes for example salts thereof with inorganic acids, suchas hydrochloride salt, sulfate salt, nitrate salt, and phosphate salt,and salts thereof with organic acids, such as methanesulfonate salt,maleate salt, fumarate salt and citrate salt.

[0071] Additionally, the solvated product thereof is prepared by addingsolvents used for the production and purification thereof, for examplewater and alcohol, to the compound I, with no specific limitation, aslong as the solvated product never disadvantageously affects the ACATinhibitory action. The solvated product is preferably a hydrated productthereof.

[0072] The invention relates to the compound represented by the generalformulae I, II, III or IV, a salt thereof or a solvated product thereof,and a pharmaceutical composition comprising the same and apharmaceutically acceptable carrier. More specifically, the inventionrelates to a pharmaceutical composition as ACAT inhibitor,intra-cellular cholesterol transfer inhibitory agent, bloodcholesterol-reducing agent, or macrophage foaming-suppressing agent.Still furthermore, the invention relates to a pharmaceutical compositionas a prophylactic and therapeutic agent of hyperlipidemia,arteriosclerosis, cerebrovascular diseases, ischemic cardiac disorders,ischemic colon disorders or aortic aneurysm.

[0073] Still additionally, the invention relates to a method fortherapeutically treating diseases due to ACAT, intra-cellularcholesterol transfer, blood cholesterol or macrophage foaming and amethod for therapeutically treating hyperlipidemia, arteriosclerosis,cerebrovascular diseases, ischemic cardiac disorders, ischemic colondisorders or aortic aneurysm, comprising administering a therapeuticallyeffective dose of the compound represented by the general formula I, II,III or IV, a salt thereof or a solvated product thereof.

[0074] Still more additionally, the invention relates to the use of thecompound represented by the general formula I, II, III or IV, a saltthereof or a solvated compound thereof for producing an ACAT inhibitor,an agent inhibiting intra-cellular cholesterol transfer, an agentreducing blood cholesterol, or an agent suppressing macrophage foamingand the use thereof for therapeutically treating hyperlipidemia,arteriosclerosis, cerebrovascular diseases, ischemic cardiac disorders,ischemic colon disorders or aortic aneurysm.

[0075] The compound I can be produced by a variety of known methods,with no specific limitation. The compound I can be produced for exampleby the following steps.

[0076] 1. Process of Producing Compound With Z Representing Single Bond

[0077] (1) Following the reaction scheme described hereinbelow, reactionof carboxylic acid represented by the general formula V or a reactivederivative thereof, for example acid halide, with amine represented bythe general formula VI generates an amide derivative represented by thegeneral formula VII. Reaction of the resulting compound represented bythe general formula VII with a compound represented by the generalformula VIII can generate the objective compound I′ with Z representingsingle bond:

[0078] wherein R₁₁ represents an elimination group; and R₁₂ represents aresidue of a reactive derivative of hydroxyl group or carboxyl group.

[0079] A general method for peptide synthesis is applicable to thereaction of the compound V with the compound VI. R₁₁ in the generalformula V is preferably halogen atom such as chlorine atom and bromineatom; and the residue of a reactive derivative as represented by R₁₂ ispreferably an acid anhydride residue of mesyl acid, tosyl acid, aceticacid and pivalic acid. For example, the two compounds react together inthe presence of a condensing agent in a solvent whereby the objectivecompound can be recovered. As the condensing agent, use may be made offor example 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) and1,3-dicyclohexylcarbodiimide (DCC), singly or in combination with1-hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (HOSU). As thesolvent, use can be made of for example dimethylformamide, methylenechloride, chloroform, tetrahydrofuran and toluene, singly or incombination thereof, with no specific limitation.

[0080] The reaction varies, depending on the raw materials to be used;the reaction proceeds generally at 0 to 100° C., preferably aroundambient temperature, for one to 30 hours, preferably 10 to 20 hours.When a highly reactive carboxylic halogenide is used as the compound V,the compound V is allowed to react with the compound VI in the presenceof bases, for example triethylamine, 4-dimethylaminopyridine orN-methylmorpholine by general methods.

[0081] The starting compounds V and VI are known compounds; the compoundV can be produced by a method comprising oxidizing haloalkyl alcoholwith Jones reagents and the like, while the compound VI can be producedby a method comprising subjecting a nitrobenzene derivative to areductive reaction including contact reduction to prepare acorresponding aniline derivative.

[0082] The reaction of the compound VII thus recovered by theaforementioned methods with the compound VIII can be progressed in thepresence or absence of bases in a solvent. As the solvent, use may bemade of those described above, including bases for example inorganicbases including alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide, alkali metal carbonates such as sodium carbonateand potassium carbonate, and alkali metal hydrogen carbonates such assodium hydrogen carbonate and potassium hydrogen carbonate; and organicbases such as pyridine, triethylamine, N,N-diisopropylethylamine,N-methylmorpholine, and N,N-dimethylaniline.

[0083] (2) Following the reaction represented by the following scheme,the compound represented by the general formula VIII is allowed to reactwith free carboxylic acid or an inactive carboxylic acid form as thecompound represented by the general formula V, to recover a carboxylatederivative represented by the general formula IX. The resulting compoundrepresented by the general formula IX or a reactive derivative thereof,for example an acid halide, is allowed to react with an anilinederivative represented by the general formula VI, to generate theobjective compound I′ with Z representing single bond:

[0084] wherein R₁₁ represents an elimination group and R₁₂ represents aresidue of a reactive derivative of hydroxyl group or carboxyl group.

[0085] The reaction of the compound VIII with the compound V can befacilitated by the second step described above in (1). The reaction isprogressed by using potassium hydroxide as the base and ethanol as thesolvent, preferably. The reaction of the compound VI with the compoundIII can be facilitated by the first step described above in (1). Ifnecessary, R₁₂ in the compound IX can be modified as a reactivederivative residue, prior to the reaction.

[0086] 2. Process of Producing Compound I″ With Z Representing —NH—.

[0087] The compound represented by the general formula I wherein Zrepresents —NH— can be produced by a variety of methods. The compoundcan be produced by the method represented by the following reactionscheme.

[0088] By allowing an isocyanate derivative represented by the generalformula X to react with an aniline derivative represented by the generalformula VI, a urea derivative represented by the general formula XI canbe recovered.

[0089] By allowing the compound VIII to react with the resulting ureaderivative, the objective compound I″ with Z representing —NH— can berecovered.

[0090] As regards the reaction of the compound X with the compound VI atthe first step, reaction of one to 2 equivalents of the compound VI withone equivalent of the compound X in a solvent can yield the compound XI.As the solvent, preferably, use is made of for example methylenechloride, chloroform, ether, tetrahydrofuran, toluene, xylene, anddimethylformamide, with no specific limitation. The reaction progressesat 0° C. to the boiling point of the solvent used, over one to 24 hours.

[0091] The isocyanate derivative represented by the general formula X isa known compound and can be produced, for example by a method comprisingallowing the carboxylic acid as the compound X to react withdiphenylphosphoryl azide in the presence of a base (the method byShioiri et al.) and a method en route of acid azide prepared by allowingan acid halide as the compound V to react with sodium azide.

[0092] The reaction of the compound XI with the compound VIII can befacilitated according to the second step of the reaction 1.1.

[0093] The intermediates and objective compounds as recovered in theindividual reactions can be isolated and purified by purificationmethods routinely used in synthetic organic chemistry, for examplefiltration, extraction, rinsing, drying, concentration,recrystallization, and various chromatographic means. Furthermore, theintermediates can be subjected, with no purification, to next reaction.

[0094] The resulting compound I can be modified as an acid addition saltin a conventional manner.

[0095] Alternatively, solvated products thereof with solvents such asreaction solvent and recrystallization solvent, specifically hydratedproduct thereof, may also be recovered.

[0096] Specific examples of the compounds recovered by the productionmethods are shown in Tables 1, 2, 3, 4, 5, 6, 7 and 8. TABLE 1 (I)

Example No.

X Y Z n Ar 1

O S * 5 2,6-diisopropylphenyl 2

O S * 5 2,6-diisopropylphenyl 3

O S * 5 2,6-diisopropylphenyl 4

O S * 5 2,6-diisopropylphenyl 5

NH S * 5 2,6-diisopropylphenyl 6

NH S * 5 2,6-diisopropylphenyl 7

O S * 8 2,6-diisopropylphenyl 8

O S * 8 2,6-diisopropylphenyl 9

O S * 8 2,6-diisopropylphenyl 10 

O S * 8 2,6-diisopropylphenyl 11 

O S * 5 2,6-diisopropylphenyl 12 

O S * 5 2,6-diisopropylphenyl

[0097] TABLE 2 Example No.

X Y Z n Ar 13

O S * 5 2,6-diisopropylphenyl 14

O S * 5 2,6-diisopropylphenyl 15

O NR* * 5 2,6-diisopropylphenyl 16

O NMe * 5 2,6-diisopropylphenyl 17

O NH * 5 2,6-diisopropylphenyl 18

O NH * 5 2,6-diisopropylphenyl 19

O NH * 5 2,6-diisopropylphenyl 20

O NH * 5 2,6-diisopropylphenyl 21

S S * 5 2,6-diisopropylphenyl 22

O S * 5 2,6-diisopropylphenyl 23

O S * 5 2,6-diisopropylphenyl 24

O S * 5 2,6-diisopropylphenyl 25

O S * 5 2,6-diisopropylphenyl

[0098] TABLE 3 Example No.

X Y Z n Ar 26

O S * 5 2,6-diisopropylphenyl 27

O S * 5 2,6-diisopropylphenyl 28

O S * 5 2,6-diisopropylphenyl 29

O S * 5 2,6-diisopropylphenyl 30

O S * 5 2,6-diisopropylphenyl 31

O S * 8 2,6-diisopropylphenyl 32

O S * 5 2,6-diisopropylphenyl 33

O S * 8 2,6-diisopropylphenyl 34

O S * 5 2,6-diisopropylphenyl 34

O S * 5 2,6-diisopropylphenyl 36

O S * 5 2,6-diisopropylphenyl 37

O S * 5 2,6-diisopropylphenyl 38

O S * 5 2,6-diisopropylphenyl 39

O S * 5 2,6-diisopropylphenyl

[0099] TABLE 4 Example No.

X Y Z n Ar 40

O S * 5 2,6-diisopropylphenyl 41

O S * 5 2,6-diisopropylphenyl 42

O S * 5 2,6-diisopropylphenyl 43

O S * 5 2,6-diisopropylphenyl 44

O S * 5 2,6-diisopropylphenyl 45

O S * 5 2,6-diisopropylphenyl 46

O S * 5 2,6-diisopropylphenyl 47

O S * 5 2,6-diisopropylphenyl 48

O S * 5 2,6-diisopropylphenyl 49

O S * 5 2,6-diisopropylphenyl 50

O S * 5 2,6-diisopropylphenyl 51

O S * 5 2,6-diisopropylphenyl

[0100] TABLE 5 Example No.

X Y Z n Ar 52

O S * 5 2,6-diisopropylphenyl 53

S S * 1 2,6-diisopropylphenyl 54

O S * 8 2,6-diisopropylphenyl 55

O S —NH— 7 2,6-diisopropylphenyl 56

O SO —NH— 7 2,6-diisopropylphenyl 57

O S —NH— 7 2,6-diisopropylphenyl 58

O SO₂ * 5 2,6-diisopropylphenyl 59

O S * 5 2,6-diisopropylphenyl 60

O S * 5 2,6-diisopropylphenyl 61

O S * 5 2,4,6-trifluorophenyl 62

O S * 5 2,4,6-trimethoxy- phenyl

[0101] TABLE 6 Example No.

X Y Z n Ar 63

NH S * 5 2,6-diisopropylphenyl 64

NH S * 5 2,6-diisopropylphenyl 65

S S * 5 2,6-diisopropylphenyl 66

O S * 5 2,6-diisopropylphenyl 67

O S * 5 2,6-diisopropylphenyl 68

NH S * 5 2,6-diisopropylphenyl 69

O S * 5 2,6-diisopropylphenyl 70

O S * 5 2,6-diisopropylphenyl 71

O S

6 2,6-diisopropylphenyl 72

O S

6 2,6-diisopropylphenyl 73

O S * 1 2,6-diisopropylphenyl 74

O S * 5 2,6-diisopropylphenyl 75

O S * 8 2,6-diisopropylphenyl

[0102] TABLE 7 Example No.

X Y Z n Ar 76

O S * 5 2,6-diisopropylphenyl 77

O S * 5 2,6-diisopropylphenyl 78

O S * 5 2,6-diisopropylphenyl 79

O S * 5 2,6-diisopropylphenyl 80

O S * 5 2,6-diisopropylphenyl 81

O S * 5 2,6-diisopropylphenyl 82

O S * 5 2,6-diisopropylphenyl 83

O S * 5 2,6-diisopropylphenyl 84

O S * 5 2,6-diisopropylphenyl 85

O S * 5 2,6-diisopropylphenyl

[0103] TABLE 8 Example No.

X Y Z n Ar 86

O S * 5 2,6-diisopropylphenyl 87

O S * 5 2,6-diisopropylphenyl 88

O S * 5 2,6-diisopropylphenyl 89

O S * 5 2,6-diisopropylphenyl 90

O S * 5 2,6-diisopropylphenyl 91

O S * 5 2,6-diisopropylphenyl 92

O S * 5 2,6-diisopropylphenyl

[0104] The inventive compound represented by the general formula I hasan ACAT inhibitory action and/or an action inhibiting intra-cellularcholesterol transfer and is therefore useful as a therapeutic agent ofhyperlipidemia or a therapeutic agent of arteriosclerosis in the fieldof clinical medicine. Particularly because the inventive compound exertsan action selectively inhibiting an ACAT type present in vascular wall,the inventive compound possibly exerts less side effects, compared withnon-selective ACAT inhibitors, which is preferable as an effectiveingredient of pharmaceutical agent.

[0105] The inventive pharmaceutical composition contains the compoundrepresented by the general formula I, an acid addition salt thereof or asolvated product thereof as the effective ingredient. Singly or incombination with other pharmaceutically acceptable carriers such asexcipients, binders and diluents, the effective ingredient can beprepared as dosage forms such as tablet, capsule, granule, powder,injection and suppository. These dosage forms can be produced accordingto known methods. For preparing an oral dosage form, the compoundrepresented by the general formula I is formulated with an appropriatecombination of excipients such as starch, mannitol and lactose, binderssuch as sodium carboxymethylcellulose and hydroxypropylcellulose,disintegrators such as crystal cellulose and carboxymethylcellulose,lubricants such as talc and magnesium stearate, and fluidity-enhancingagents such as light silicic anhydride.

[0106] The inventive pharmaceutical composition is administered orallyor parenterally.

[0107] The dose of the inventive pharmaceutical composition varies,depending on the body weight, age, sex and diseased conditions of apatient. For an adult, generally, the compound represented by thegeneral formula I is preferably administered at 1 to 1000 mg, preferably5 to 200 mg per day in one to three dividend doses.

[0108] The ACAT inhibitory action of the inventive compound representedby the general formula I is tested in the following experimentalexamples.

EXPERIMENTAL EXAMPLE 1 ACAT Inhibitory Action

[0109] In a conventional manner, microsome was prepared from thethoracic aorta of a rabbit fed with a 1% cholesterol diet for 8 weeks,which was then suspended in 0.15 M phosphate buffer, pH 7.4, to preparean enzyme solution. An enzyme solution was prepared from a rabbit smallintestine on normal diet, which was defined as an enzyme solutionderived from small intestine.

[0110] The ACAT inhibitory activity was assayed by a modification of themethod by J. G. Hyder, J. Lipid Res., 24, 1127-1134 (1983). Morespecifically, 2 μl of a test compound dissolved in dimethyl sulfoxide(DMSO) was added to 88 μl of 0.15 M phosphate buffer, pH 7.4 containing¹⁴C-Oleoyl-CoA (40 μM, 60,000 dpm) and 2.4 mg/ml bovine serum albumin,for incubation at 37° C. for 5 minutes. 10 μl of an enzyme solution wasadded to the resulting solution for reaction at 37° C. for 5 days (smallintestine-derived enzyme solution was subjected to reaction for 3minutes). Subsequently, the reaction was terminated by adding 3 ml ofchloroform/methanol (2/1) and 0.5 ml of 0.04 N hydrochloric acid to thereaction solution, to extract lipid. The solvent layer was concentratedand dried, which was then dissolved in hexane and spotted on a TLC plate(manufactured by Merck, Co.). The plate was eluted withhexane:ether:acetic acid (75:25:1). The radioactivity of the resultingcholesterol ester fraction was assayed by BAS 2000 (manufactured by FujiPhoto Film, Co., Ltd.). Compared with the radioactivity of a controlprepared by single addition of DMSO, IC₅₀ was determined. The resultsare shown in Table 9. TABLE 9 A B C D  1 0.025 0.14 5.6  6 0.60 1.0 1.727 0.042 0.32 7.6 28 0.029 0.12 4.1 29 0.042 0.054 1.3 34 0.070 0.21 3.038 0.25 0.17 0.7 46 0.032 0.33 10.3 50 0.036 0.077 2.1 Control 1 0.450.87 1.9 Control 2 0.047 0.13 2.8 Control 3 0.034 0.056 1.7 Control 40.026 0.037 1.4

EXPERIMENTAL EXAMPLE 2 ACAT Inhibitory Action (Anti-foaming Action) inJ1744 Cells and HepG2 Cells

[0111] J774 cells or HepG2 cells were inoculated on a 24-well plate;J774 cells and HepG2 cells were cultured in DMEM and MEM culture broths(each of the broths containing 10% calf fetus serum), respectively, in a5% CO₂ incubator at 37° C. for 24 hours. These culture broths wereindividually exchanged to 0.5 ml of DMEM and MEM containing 10 μg/ml25-OH cholesterol and a test sample, for 18-hr culturing. Afterdiscarding the culture media, the resulting cultures were rinsed twicewith PBS and extracted with 1.5 ml of hexane:isopropanol (3:2), forconcentration and drying. The extracts were dissolved in isopropanolcontaining 0.2 ml of 10% Triton X-100, to assay total cholesterol (TC)and free cholesterol (FC) by using Cholesterol E Test WAKO (manufacturedby Wako Pure Chemicals, Co.) and Free Cholesterol E Test Wako(manufactured by Wako Pure Chemicals, Co.). After extraction, cellularresidue was solubilized in 0.25 ml of 2 N NaOH at 37° C. for 30 minutes,to assay protein by BCA Protein Assay Reagent (Pierce). Based on thedifference between TC and FC, cholesterol ester was calculated perprotein, to determine IC₅₀, compared with the calculated control IC₅₀value. The results are shown in Table 10. TABLE 10 A B C D  1 1.30 4.13.2  6 10.0 10.0 1.0 27 1.31 — — 28 0.47 0.42 0.9 29 0.26 1.9 7.3 340.60 8.15 13.5 38 1.83 — — 46 0.098 29.76 303.4 50 0.82 0.72 0.9 750.012 0.089 7.4 88 1.64 10.0 6.1 Control 1 0.56 5.30 9.5 Control 2 0.581.1 1.9 Control 3 0.32 1.3 4.3 Control 4 0.12 0.75 6.3

[0112] The following compounds were tested as control compounds by thesame method. The results are shown in Tables 7 and 8.

[0113] Control 1:

[0114]5-[2-(2-(4-fluorophenyl)ethyl)-3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran-6-yl]oxy-2,2-dimethyl-N-(2,6-diisopropylphenyl)pentanamide(WO92/09582)

[0115] Control 2:

[0116](+)-(S)-2-[5-(3,5-dimethylpyrazol-1-yl)pentasulfinyl]-4,5-diphenylimidazole(EP, A, 523941)

[0117] Control 3:

[0118] N-(2,2,5,5-tetramethyl-1,3-dioxan-4-ylcarbonyl)-β-alanine2(S)-[N′-(2,2-dimethylpropyl)-N′-nonylureido]-1(S)-cyclohexyl ester (EP,A, 421441)

[0119] Control 4:

[0120][5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptyl-2-benzoxazolamine(WO93/23392)

EXAMPLES

[0121] The inventive compounds are specifically described below. Theinvention is not limited to these specific examples.

Example 1

[0122] Production of6-(oxazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0123] Potassium carbonate (64 mg, 0.47 mmol) and 18-crown-6 (11 mg,0.04 mmol) were added to a solution of 2-mercaptooxazolo[4,5-b]pyridine(64 mg, 0.42 mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (150mg, 0.42 mmol) in DMF (3 ml), and the resulting mixture was stirred at80° C. for 4 hours. After the reaction solution was diluted with water,the organic layer was extracted with ethyl acetate. The organic layerwas washed with water and dried over anhydrous magnesium sulfate, fromwhich the solvents were distilled off. The residue was purified bysilica gel column chromatography (elution solvents:hexane:ethylacetate=2:1); the resulting crystal was recrystallized from ethylacetate-hexane, to recover the objective compound of 49 mg (at a yieldof 27%) as a colorless needle-like crystal.

[0124] Melting Point: 94-95° C.

[0125] IR (KBr) cm⁻¹: 3230, 2965, 1646, 1497, 1403.

[0126] 1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.52-1.68 (2H, m),1.68-1.82 (2H, m), 1.82-1.97 (2H, m), 2.33-2.45 (2H, m), 3.11 (2H, sept,J=6.8 Hz), 3.43 (2H, t, J=7.0 Hz), 7.12 (1H, d, J=8.1 Hz), 7.12 (1H, d,J=6.6 Hz), 7.22 (1H, dd, J=8.1, 6.6 Hz), 7.31 (1H, dd, J=8.1, 4.8 Hz)7.98 (1H, dd, J=8.1, 1.5 Hz), 8.42 (1H, d, J=4.8 Hz), 8.72 (1H, br s).

[0127] EIMS m/z (relative intensity): 425 (M⁺), 407 (100).

[0128] Elementary Analysis: C₂₄H₃₁N₃O₂S Required: C, 67.73; H, 7.34; N,9.87; S, 7.53. Found: C, 67.68; H, 7.33; N, 9.86; S, 7.57.

Example 2

[0129] Production of6-(oxazolo[4,5-c]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0130] In the same manner as in Example 1 except for the use of2-mercaptooxazolo[4,5-c]pyridine instead of2-mercaptooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

[0131] Melting Point: 126-127° C.

[0132] IR (KBr) cm⁻¹: 3239, 2963, 1645, 1494, 1460.

[0133] 1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.9 Hz), 1.52-1.65 (2H, m),1.67-1.80 (2H, m), 1.83-1.96 (2H , m), 2.33-2.43 (2H, m), 3.11 (2H,sept, J=6.9 Hz), 3.42 (2H, t, J=7.1 Hz), 7.12 (1H, d, J=8.3 Hz), 7.12(1H, d, J=6.9 Hz), 7.22 (1H, dd, J=8.3, 6.9 Hz), 7.66 (1H, dd, J=5.5,1.0 Hz) 8.49 (1H, d, J=5.5 Hz), 8.72 (1H, br s), 8.89 (1H, s).

[0134] EIMS m/z (relative intensity): 425 (M⁺,100).

[0135] Elementary Analysis: C₂₄H₃₁N₃O₂S Required: C, 67.73; H, 7.34; N,9.87; S, 7.53. Found: C, 67.65; H, 7.40; N, 9.59; S, 7.44.

Example 3

[0136] Production of6-(oxazolo[5,4-c]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0137] In the same manner as in Example 1 except for the use of2-mercaptooxazolo[5,4-c]pyridine instead of2-mercaptooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

[0138] Melting Point: 164-165° C.

[0139] IR (KBr) cm⁻¹: 3227, 2963, 1652, 1482, 1115.

[0140] 1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.53-1.67 (2H, m),1.67-1.82 (2H, m), 1.84-1.96 (2H, m), 2.33-2.42 (2H, m), 3.11 (2H, sept,J=6.8 Hz), 3.44 (2H, t, J=7.2 Hz), 7.12 (1H, d, J=8.4 Hz), 7.12 (1H, d,J=6.7 Hz), 7.22 (1H, dd, J=8.4, 6.7 Hz), 7.63 (1H, dd, J=5.4, 1.0 Hz)8.49 (1H, d, J=5.4 Hz), 8.71 (1H, br s), 8.89 (1H, d, J=0.7 Hz).

[0141] EIMS m/z (relative intensity): 425 (M⁺), 230 (100).

[0142] Elementary Analysis: C₂₄H₃₁N₃O₂S Required: C, 67.73; H, 7.34; N,9.87, S, 7.53. Found: C, 67.84; H, 7.43; N, 9.74, S, 7.51.

Example 4

[0143] Production of6-(oxazolo[5,4-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0144] In the same manner as in Example 1 except for the use of2-mercaptooxazolo[5,4-b]pyridine instead of2-mercaptooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

[0145] Melting Point: 146-147° C.

[0146] IR (KBr) cm⁻¹: 3252, 2967, 1648, 1492, 1207.

[0147] 1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.53-1.67 (2H, m),1.67-1.81 (2H, m), 1.83-1.96 (2H, m), 2.43-2.55 (2H, m), 3.11 (2H, sept,J=6.8 Hz), 3.40 (2H, t, J=7.2 Hz), 7.12 (1H, d, J=8.6 Hz), 7.12 (1H, d,J=6.7 Hz), 7.22 (1H, dd, J=8.6, 6.7 Hz), 7.40 (1H, dd, J=7.8, 5.1 Hz)8.01 (1H, dd, J=7.8, 1.6 Hz), 8.22 (1H, dd, J=5.1, 1.6 Hz), 8.71 (1H, brs).

[0148] EIMS m/z (relative intensity): 425 (M⁺), 176 (100).

[0149] Elementary Analysis: C₂₄H₃₁N₃O₂S Required: C, 67.73; H, 7.34; N,9.87; S, 7.53. Found: C, 67.84; H, 7.44; N, 9.63; S, 7.50.

Example 5

[0150] Production of6-(imidazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0151] Potassium carbonate (86 mg, 0.62 mmol) and 18-crown-6 (15 mg,0.06 mmol) were added to a solution of2-mercaptoimidazolo[4,5-b]pyridine (85 mg, 0.56 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (200 mg, 0.56 mmol) in DMF(4 ml), and the resulting mixture was stirred at 80° C. for 4 hours.After the reaction solution was diluted with water, the organic layerwas extracted with ethyl acetate. The organic layer was washed withwater and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (elution solvents:chloroform:methanol=100:1); theresulting crystal was recrystallized from chloroform-ethylacetate-hexane, to recover the objective compound of 73 mg (at a yieldof 31%) as a colorless needle-like crystal.

[0152] Melting Point: 227-229° C.

[0153] IR (KBr) cm⁻¹: 3235, 2963, 1651, 1395, 1268.

[0154] 1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.51-1.89 (6H, m),2.38 (2H, m), 3.11 (2H, sept, J=6.8 Hz), 3.36 (2H, t, J=7.1 Hz), 7.11(1H, dd, J=8.3, 4.9 Hz), 7.11 (1H, d, J=8.3 Hz), 7.12 (1H, d, J=6.6 Hz),7.22 (1H, dd, J=8.3, 6.6 Hz), 7.77 (1H, d, J=8.3 Hz) 8.19 (1H, d, J=4.9Hz), 8.72 (1H, br s).

[0155] EIMS m/z (relative intensity): 424 (M⁺), 165 (100).

[0156] Elementary Analysis: C₂₄H₂N₄OS Required: C, 67.89; H, 7.60; N,13.20; S, 7.55. Found: C, 68.01; H, 7.62; N, 12.96; S, 7.41.

Example 6

[0157] Production of6-(imidazolo[4,5-c]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0158] In the same manner as in Example 5 except for the use of2-mercaptoimidazolo[4,5-c]pyridine instead of2-mercaptoimidazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

[0159] Melting Point: 96-98° C.

[0160] IR (KBr) cm⁻¹: 3231, 2962, 1649, 1463, 1278.

[0161] 1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.51-1.89 (6H, m),2.38 (2H, m), 3.11 (2H, sept, J=6.8 Hz), 3.36 (2H, t, J=5.6 Hz), 7.12(1H, d, J=8.3 Hz), 7.12 (1H, d, J=6.6 Hz), 7.22 (1H, dd, J=8.3, 6.6 Hz),7.40 (1H, dd, J=5.6, 1.0 Hz) 8.19 (1H, d , J=5.6 Hz), 8.70 (1H, d, J=1.0Hz), 8.71 (1H, br s).

[0162] EIMS m/z (relative intensity): 424 (M⁺), 165 (100).

[0163] Elementary Analysis: C₂₄H₃₂N₄OS Required: C, 67.89; H, 7.60; N,13.20; S, 7.55. Found: C, 67.95; H, 7.66; N, 12.92; S, 7.33.

Example 7

[0164] Production of9-(oxazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

[0165] In the same manner as in Example 1 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless amorphous.

[0166] IR (KBr)cm⁻¹: 3435, 3234, 2926, 1647, 1494, 1402.

[0167] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.39-1.72 (10H, m),1.85 (2H, quint, J=7.2 Hz), 2.34 (2H, m), 3.10 (2H, sept, J=6.8 Hz),3.39 (2H, t, J=7.2 Hz), 7.10 (1H, d, J=8.6 Hz), 7.11 (1H, d, J=6.8 Hz),7.21 (1H, dd, J=8.6, 6.8 Hz), 7.30 (1H, dd, J=8.1, 5.0 Hz), 7.97 (1H,dd, J=8.1, 1.5 Hz), 8.41 (1H, dd, 5.0, 1.5 Hz),8.68 (1H, br s).

[0168] EIMS m/z (relative intensity): 467 (M⁺, 100).

[0169] Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N,8.99; S, 6.86. Found: C, 69.39; H, 8.05; N, 8.85; S, 6.56.

Example 8

[0170] Production of9-(oxazolo[4,5-c]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

[0171] In the same manner as in Example 6 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

[0172] Melting Point: 74-75° C.

[0173] IR (KBr) cm⁻¹: 3434, 3237, 2928, 1647, 1107.

[0174] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.38-1.71 (10H, m),1.84 (2H, quint, J=7.3 Hz), 2.34 (2H, m), 3.10 (2H, sept, J=6.8 Hz),3.38 (2H, t, J=7.3 Hz), 7.11 (1H, d, J=8.3 Hz), 7.11 (1H, d, J=6.8 Hz),7.21 (1H, dd, J=8.3, 6.8 Hz), 7.64 (1H, dd, J=5.4, 0.7 Hz), 8.47 (1H, d,J=5.4 Hz), 8.68 (1H, br s), 8.88 (1H, d, 0.7 Hz).

[0175] EIMS m/z (relative intensity): 467 (M⁺), 217(100).

[0176] Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N,8.99; S, 6.86. Found: C, 69.28; H, 8.00; N, 8.85; S, 6.80.

Example 9

[0177] Production of9-(oxazolo[5,4-c]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

[0178] In the same manner as in Example 3 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

[0179] Melting Point: 81-82° C.

[0180] IR (KBr)cm⁻¹: 3435, 3259, 2927, 1647, 1480.

[0181] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=7.1 Hz), 1.39-1.69 (10H, m),1.85 (2H, quint, J=7.2 Hz), 2.34 (2H,m), 3.10 (2H, sept, J=7.1 Hz), 3.40(2H, t, J=7.2 Hz), 7.11 (1H, d, J=8.5 Hz), 7.11 (1H, d, J=6.8 Hz), 7.21(1H, dd, J=8.5, 6.8 Hz), 7.62 (1H, dd, J=5.1, 1.0 Hz), 8.47 (1H, d,J=5.1 Hz), 8.83 (1H, br s), 8.88 (1H, d, 1.0 Hz).

[0182] EIMS m/z (relative intensity): 467 (M⁺), 217(100).

[0183] Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N,8.99; S, 6.86. Found: C, 69.37; H, 8.03; N, 8.85; S, 6.82.

Example 10

[0184] Production of9-(oxazolo[5,4-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

[0185] In the same manner as in Example 4 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless oil.

[0186] IR (cap) cm⁻¹: 3253, 2962, 2929, 1651, 1489, 1210.

[0187] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.38-1.69 (10H, m),1.84 (2H, quint, J=7.1 Hz), 2.34 (2H,m), 3.10 (2H, sept, J=6.8 Hz), 3.37(2H, t, J=7.1 Hz), 7.10 (1H, d, J=8.6 Hz), 7.11 (1H, d, J=6.6 Hz), 7.21(1H, dd, J=8.6, 6.6 Hz), 7.38 (1H, dd, J=7.8, 4.9 Hz), 8.00 (1H, dd,J=7.8, 1.5 Hz), 8.21 (1H, dd, 4.9, 1.5 Hz), 8.68 (1H, br s).

[0188] EIMS m/z (relative intensity): 467 (M⁺, 100).

[0189] Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N,8.99; S, 6.86. Found: C, 69.60; H, 8.20; N, 8.58; S, 6.86.

Example 11

[0190] Production of6-(5-methyloxazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0191] 10% palladium-carbon (200 mg) was added to an ethanol suspension(50 ml) of 3-hydroxy-6-methyl-2-nitropyridine (2.0 g, 13.0 mmol), withstirring in hydrogen gas atmosphere for 90 minutes. After reaction, thecatalyst palladium-carbon was filtered off.

[0192] To the resulting ethanol solution of2-amino-3-hydroxy-6-methylpyridine was added potassium o-ethyldithiocarbonate (4.16 g, 26.0 mmol), for heating under reflux for 17hours to distill off the solvent. The residue was dissolved in water.Through addition of acetic acid, the resulting solution was adjusted topH 5. The deposited crystal was filtered and washed with water, andthen, the resulting crystal was dried under heating at 80° C.

[0193] Potassium carbonate (86 mg, 0.62 mmol) and 18-crown-6 (15 mg,0.06 mmol) were added to a solution of the resulting2-mercapto-5-methyl-oxazolo[4,5-b]pyridine (94 mg, 0.56 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (200 mg, 0.5 mmol) in DMF (4ml), and the resulting mixture was stirred at 80° C. for 4 hours. Afterthe reaction solution was diluted with water, the organic layer wasextracted with ethyl acetate. The organic layer was washed with waterand dried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (elution solvents:chloroform:methanol=20:1); theresulting crystal was recrystallized from methanol-ethyl acetate-hexane,to recover the objective compound of 150 mg (at a yield of 61%) as acolorless needle-like crystal.

[0194] Melting Point: 145-146° C.

[0195] IR (KBr) cm⁻¹: 3229, 2963, 1645, 1504, 1400.

[0196] 1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.55-1.93 (6H,m),(2H, m), 2.56 (3H, s), 1.15 3.11 (2H, sept, J=6.8 Hz), 3.40 (2H, t,J=7.1 Hz), 1.16 7.12 (1H, d, J=8.5 Hz), 7.12 (1H, d, J=6.6 Hz), 7.16(1H, d, J=8.3 Hz), 7.22 (1H, dd, J=8.5, 6.6 Hz), 7.84 (1H, d, J=8.3 Hz),8.72 (1H, br s).

[0197] EIMS m/z (relative intensity): 439 (M⁺), 230 (100).

[0198] Elementary Analysis: C₂₅H₃₃N₃O₂S Required: C, 68.30; H, 7.57; N,9.56; S, 7.29. Found: C, 68.14; H, 7.60; N, 9.45; S, 7.31.

Example 12

[0199] Production of6-(4-methyloxazolo[5,4-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0200] In the same manner as in Example 11 except for the use of2-hydroxy-4-methyl-3-nitropyridine instead of3-hydroxy-6-methyl-2-nitropyridine, reaction progressed to recover theobjective compound as a colorless crystal.

[0201] Melting Point: 157-158° C.

[0202] IR (KBr) cm⁻¹: 3430, 3261, 1648, 1533.

[0203] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=7.1 Hz), 1.53-1.94 (6H, m),2.38 (2H, m), 2.53 (3H, s), 3.09 (2H, sept, J=7.1 Hz), 3.37 (2H, t,J=7.2 Hz), 7.08 (1H, d, J=8.8 Hz), 7.09 (1H, d, J=6.6 Hz), 7.17 (1H, dd,J=4.9, 0.7 Hz), 7.19 (1H, dd, J=8.8, 6.6 Hz), 8.04 (1H, d, J=4.9 Hz),8.64 (1H, br s).

[0204] EIMS m/z (relative intensity): 439 (M⁺, 100).

[0205] Elementary Analysis: C₂₅H₃₃N₃O₂ S

[0206] Required: C, 68.30; H, 7.57; N, 9.56; S, 7.29. Found: C, 68.14;H, 7.53; N, 9.43; S, 7.26.

Example 13

[0207] Production of6-(7-methyloxazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0208] In the same manner as in Example 11 except for the use of2-amino-3-hydroxy-4-methylpyridine instead of2-amino-3-hydroxy-6-methylpyridine, reaction progressed to recover theobjective compound as a colorless crystal.

[0209] Melting Point: 145-147° C.

[0210] IR (KBr) cm⁻¹: 3234, 2962, 1647, 1500, 1124.

[0211] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.55-1.63 (2H, m),1.70-1.79 (2H, m), 1.87-1.95 (2H, m), 2.35-2.42 (2H, m), 2.50 (3H, s),3.10 (2H, sept, J=6.8 Hz), 3.41 (2H, t, J=7.2 Hz), 7.11 (1H, d, J=7.8Hz), 7.11 (1H, d, J=7.6 Hz), 7.14 (1H, dd, J=5.1, 0.7 Hz), 7.22 (1H, dd,J=7.8, 7.6 Hz), 8.27 (1H, d, J=5.1 Hz), 8.73 (1H, br s).

[0212] EIMS m/z (relative intensity): 439 (M⁺), 230 (100).

[0213] Elementary Analysis: C₂₆H₃₃N₃O₂S Required: C, 68.30; H, 7.57; N,9.56; S, 7.29. Found: C, 68.13; H, 7.62; N, 9.28; S, 7.14.

Example 14

[0214] Production of6-(5,7-dimethyloxazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0215] In the same manner as in Example 11 except for the use of2-amino-4,6-dimethyl-3-hydroxypyridine instead of2-amino-3-hydroxy-6-methylpyridine, reaction progressed to recover theobjective compound as a colorless crystal.

[0216] Melting Point: 169-171° C.

[0217] IR (KBr) cm⁻: 3206, 2966, 1641, 1503, 1114.

[0218] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.52-1.62 (2H, m),1.68-1.78 (2H, m), 1.84-1.94 (2H, m), 2.36-2.47 (2H, m), 2.48 (3H, s),2.50 (3H, s), 3.09 (2H, sept, J=6.8 Hz), 3.38 (2H, t, J=7.1 Hz), 6.99(1H, s), 7.11 (1H, d, J=7.8 Hz), 7.11 (1H, d, J=7.6 Hz), 7.21 (1H, dd,J=7.8, 7.6 Hz), 8.72 (1H, br s).

[0219] EIMS m/z (relative intensity): 453 (M⁺), 181 (100).

[0220] Elementary Analysis: C₂₆H₃₅N₃O₂S Required: C, 68.84; H, 7.78; N,9.26; S, 7.07. Found: C, 68.95; H, 7.77; N, 9.17; S, 7.10.

Example 15

[0221] Production of6-(N-dimethylphenylsilylmethyl-N-oxazolo[4,5-b]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide

[0222] Potassium carbonate (42 mg, 0.3 mmol) and 18-crown-6 (5 mg, 0.02mmol) were added to a solution of6-(oxazolo[4,5-b]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide(78 mg, 0.19 mmol) and chloromethyldimethylphenylsilane (42 mg, 0.23mmol) in DMF (2 ml), and the resulting mixture was stirred at 80° C. for2 hours. After the reaction solution was diluted with water, the organiclayer was extracted with ether. The organic layer was washed with waterand dried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by preparative thin layerchromatography (elution solvents:hexane:acetone=5:3), to recover theobjective compound of 47 mg (at a yield of 44%) as a colorless oil.

[0223] IR (cap) cm⁻¹: 3252, 2962, 1645, 1563, 1413.

[0224] 1H-NMR (d₆-DMSO) δ: 0.38 (6H, s), 1.11 (12H, d, J=6.8 Hz),1.30-1.40 (2H, m), 1.58-1.72 (4H, m), 2.31 (2H, t, J=7.3 Hz), 3.07 (2H,sept, J=6.8 Hz), 3.36 (2H, s), 3.43 (2H, t, J=6.8 Hz), 6.86 (1H, dd,J=7.8, 5.1 Hz), 7.09 (1H, d, J=8.3 Hz), 7.09 (1H, d, J=7.1 Hz), 7.19(1H, dd, J=8.3, 7.1 Hz), 7.30-7.35 (3H, m), 7.46 (1H, dd, J=7.8, 1.5Hz), 7.54-7.58 (2H, m), 8.05 (1H, dd, J=5.1, 1.5 Hz), 8.64 (1H, br s).

[0225] EIMS m/z (relative intensity): 541 (M⁺—Me), 135 (100).

[0226] Elementary Analysis: C₃₃H₄₄N₄O₂ Si Required: C, 71.18; H, 7.96;N, 10.06. Found: C, 70.94; H, 8.02; N, 10.12.

Example 16

[0227] Production of6-(N-methyl-N-oxazolo[4,5-b]pyridin-2-yl-amino)-N-(2,6-diisopropylphenyl)hexanamide

[0228] Potassium carbonate (152 mg, 1.1 mmol) and 18-crown-6 (26.4 mg,0.1 mmol) were added to a solution of the resulting6-bromo-N-(2,6-diisopropylphenyl)hexanamide (354 mmol, 1.0 mmol) andN-benzylmethylamine (121 mg, 1.0 mmol) in DMF (5 ml), and the resultingmixture was stirred at 80° C. for 2 hours. After the reaction solutionwas diluted with water, the organic layer was extracted with ether. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (20 g of silica gel;elution solvents:chloroform:methanol=30:1); the resulting crystal wasrecrystallized from acetone-ether-methanol, to recover the objectivecompound of 235 mg (at a yield of 60%) as a colorless needle-likecrystal. To a solution in ethanol (5 ml) of the benzylmethylaminoanilide(220 mg, 0.56 mmol) were added a catalytic amount of conc. hydrochloricacid (0.05 ml) and 10% palladium-carbon catalyst (100 mg), and theresulting mixture was stirred at ambient temperature in hydrogenatmosphere for 15 hours. The reaction solution was filtered throughcelite. The resulting filtrate was concentrated under reduced pressure,which was then diluted with ethyl acetate. The organic layer wassequentially washed with an aqueous saturated sodium hydrogen carbonatesolution and saturated sodium chloride solution, and was then dried overanhydrous magnesium sulfate, from which the solvents were distilled offto recover 6-methylamino-N-(2,6-diisopropylphenyl)hexanamide (145 mg ata yield of 85%) as a solid material. The methylaminoanilide (120 mg,0.39 mmol) and 2-methyloxazolo[4,5-b]pyridine (50 mg, 0.3 mmol) weremixed together and stirred at 100° C. for 3 hours. The reaction residuewas purified by silica gel column chromatography (12 g of silica gel;elution solvents:hexane:acetone=5:3). The resulting crystal wasrecrystallized from acetone-ether-hexane, to recover the objectivecompound (97 mg at a yield of 76%) as a colorless crystal.

[0229] Melting Point: 162-164° C.

[0230] IR (KBr) cm⁻¹: 3435, 3230, 1656, 1562, 1412.

[0231] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.40-1.50 (2H, m),1.67-1.79 (4H, 2.35 (2H, t, J=6.8 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.18(3H, s), 3.57 (2H, t, J=7.1 Hz), 6.90 (1H, dd, J=7.8, 5.1 Hz), 7.09 (1H,d, J=8.1 Hz), 7.09 (1H, d, J=6.8 Hz), 7.19 (1H, dd, J=8.1, 6.8 Hz), 7.57(1H, dd, J=7.8, 1.5 Hz), 8.09 (1H, dd, J=5.1, 1.5 Hz), 8.65 (1H, br s).

[0232] EIMS m/z (relative intensity): 422 (M⁺), 176 (100).

[0233] Elementary Analysis: C₂₅H₃₄N₄O₂ Required: C, 71.06; H, 8.11; N,13.26. Found: C, 71.04; H, 8.27; N, 13.05.

Example 17

[0234] Production of6-(oxazolo[4,5-b]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide

[0235] 2-Methylthiooxazolo[4,5-b]pyridine (65.0 mg, 0.39 mmol) and6-amino-N-(2,6-diisopropylphenyl)hexanamide (114 mg, 0.39 mmol) weremixed together and stirred at 90° C. for 2 hours. The reaction mixturewas purified by preparative thin layer chromatography (elutionsolvents:hexane:acetone=5:3). The resulting crude crystal wasrecrystallized from dichloromethane-ether-hexane, to recover theobjective compound as a colorless needle-like crystal.

[0236] Melting Point: 152-153° C.

[0237] IR (KBr) cm⁻¹: 3416, 2964, 1656, 1571, 1413.

[0238] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.43-1.57 (2H, m),1.64-1.77 (4H, 2.35 (2H, t, J=7.3 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.38(2H, dd, J=12.9, 6.8 Hz), 6.89 (1H, dd, J=7.8, 5.1 Hz), 7.09 (1H, d,J=8.3 Hz), 7.09 (1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz), 7.53(1H, dd, J=7.8, 1.5 Hz), 7.87 (1H, br s), 8.06 (1H, dd, J=5.1, 1.5 Hz),8.65 (1H, br s).

[0239] EIMS m/z (relative intensity): 408 (M⁺, 100).

[0240] Elementary Analysis: C₂₄H₃₂N₄O₂ Required: C, 70.56; H, 7.89; N,13.71. Found: C, 70.70; H, 7.87; N, 13.51.

Example 18

[0241] Production of6-(oxazolo[4,5-c]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide

[0242] In the same manner as in Example 17 except for the use of2-methylthiooxazolo[4,5-c]pyridine instead of2-methylthiooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

[0243] Melting Point: 170-171° C.

[0244] IR (KBr) cm⁻¹: 3258, 2966, 1648, 1578, 1465.

[0245] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=7.1 Hz), 1.44-1.54 (2H, m),1.63-1.75 (4H, 2.35 (2H, t, J=6.8 Hz), 3.08 (2H, sept, J=7.1 Hz), 3.37(2H, dd, J=12.9, 6.8 Hz), 7.09 (1H, d, J=8.3 Hz), 7.09 (1H, d, J=7.1Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz), 7.31 (1H, dd, J=5.1, 0.7 Hz), 7.73(1H, br s), 8.17 (1H, d, J=5.1 Hz), 8.46 (1H, d, J=0.7 Hz), 8.67 (1H, brs).

[0246] EIMS m/z (relative intensity): 408 (M⁺), 162 (100).

[0247] Elementary Analysis: C₂₄H₃₂N₄O₂ Required: C, 70.56; H, 7.89; N,13.71. Found: C, 70.63; H, 7.96; N, 13.54.

Example 19

[0248] Production of6-(oxazolo[5,4-c]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide

[0249] In the same manner as in Example 17 except for the use of2-methylthiooxazolo[5,4-c]pyridine instead of2-methylthiooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

[0250] Melting Point: 189-190° C.

[0251] IR (KBr) cm⁻¹: 3231, 2963, 1664, 1577, 1468.

[0252] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.43-1.52 (2H, m),1.64-1.75 (4H, m), 2.35 (2H, t, J=6.3 Hz), 3.08 (2H, sept, J=6.8 Hz),3.38 (2H, dd, J=12.9, 6.8 Hz), 7.09 (1H, d, J=8.3 Hz), 7.09 (1H, d,J=7.1 Hz), 7.18 (1H, dd, J=5.4, 0.7 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz),7.98 (1H, br s), 8.21 (1H, d, J=5.4 Hz), 8.45 (1H, d, J=0.7 Hz), 8.67(1H, br s).

[0253] EIMS m/z (relative intensity): 408 (M⁺), 162 (100).

[0254] Elementary Analysis: C₂₄H₃₂N₄O₂ Required: C, 70.56; H, 7.89; N,13.71. Found: C, 70.40; H, 7.96; N, 13.55.

Example 20

[0255] Production of6-(oxazolo[5,4-b]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide

[0256] In the same manner as in Example 17 except for the use of2-methylthiooxazolo[5,4-b]pyridine instead of2-methylthiooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

[0257] Melting Point: 177-178° C.

[0258] IR (KBr) cm⁻¹: 3232, 2962, 1660, 1585, 1404.

[0259] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.45-1.54 (2H, m),1.64-1.76 (4H, 2.35 (2H, t, J=6.8 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.37(2H, dd, J=12.9, 6.8 Hz), 7.09 (1H, d, J=8.3 Hz), 7.09 (1H, d, J=6.8Hz), 7.09 (1H, dd, J=7.6, 5.1 Hz), 7.19 (1H, dd, J=8.3, 6.8 Hz), 7.48(1H, dd, J=7.6, 0.5 Hz), 7.73 (1H, br s), 7.79 (1H, dd, J=5.1, 0.5 Hz),8.64 (1H, br s).

[0260] Elementary Analysis: C₂₄H₃₂N₄O₂ Required: C, 70.56; H, 7.89; N,13.71. Found: C, 70.68; H, 7.97; N, 13.44.

Example 21

[0261] Production of6-(thiazolo[5,4-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0262] Potassium carbonate (46 mg, 0.33 mmol) and 18-crown-6 (8 mg, 0.03mmol) were added to a solution in DMF (2 ml) of2-mercaptothiazolo[5,4-b]pyridine (51 mmol, 0.3 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (106 mg, 0.3 mmol), and theresulting mixture was stirred at 80° C. for one hour. After the reactionsolution was diluted with water, the organic layer was extracted withethyl acetate. The organic layer was washed with water and dried overanhydrous magnesium sulfate, from which the solvents were distilled off.The residue was purified by silica gel column chromatography (elutionsolvents:chloroform:methanol=50:1); the resulting crystal wasrecrystallized from acetone-ether-hexane, to recover the objectivecompound of 108 mg (at a yield of 82%) as a colorless needle-likecrystal.

[0263] Melting Point: 137-138° C.

[0264] IR (KBr) cm⁻¹: 3436, 3233, 1647, 1435, 1377.

[0265] 1H-NMR (d₆-DMSO) d :δ 1.12 (12H, d, J=6.8 Hz), 1.52-1.60 (2H, m),1.70-1.78 (2H, m), 1.82-1.90 (2H, m), 2.37 (2H, t, J=6.8 Hz), 3.08 (2H,sept, J=6.8 Hz), 3.41 (2H, t, J=7.3 Hz), 7.10 (1H, d, J=7.6 Hz), 7.2(1H, t, J=7.6 Hz), 7.47 (1H, dd, J=8.3, 4.6 Hz), 8.14 (1H, dd, J=8.3,1.5 Hz) 8.45 (1H, dd, J=4.6, 1.5 Hz), 8.71 (1H, br s).

[0266] Elementary Analysis: C₂₄H₃₁N₃OS₂ Required: C, 65.27; H, 7.07; N,9.51; S, 14.52. Found: C, 65.46; H, 7.13; N, 9.33; S, 14.24.

Example 22

[0267] Production of6-(4-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0268] 2-Nitro-3-benzyloxyphenol (334 mg, 1.36 mmol) was dissolved inacetic acid (3 ml) under heating, followed by addition of zinc (1.78 g,27.2 mmol), and the resulting mixture was stirred at ambient temperaturefor one hour. After the reaction solution was diluted with water, theorganic layer was extracted with ethyl acetate. The organic layer waswashed sequentially with sodium hydrogen carbonate, water and saturatedsodium chloride solution, and was dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (50 g of silica gel;elution solvents:hexane:acetone=20:3 to 5:1) and solidified fromacetone-hexane, to recover 2-amino-3-benzyloxyphenol (155 mg at a yieldof 53%) as a brown powder.

[0269] To a solution in ethanol (10 ml) of the aminophenol (135 mg,0.627 mmol) was added potassium o-ethyl dithiocarbonate (151 mg, 0.941mmol), and the resulting mixture was refluxed under heating for 24hours. After the solution was left to stand for cooling, the solventswere distilled off under reduced pressure; to the resulting residue wasadded 1 N hydrochloric acid to adjust the solution to acidity, toextract the organic layer. The organic layer was washed with saturatedsodium chloride solution and dried over anhydrous sodium sulfate, fromwhich the solvents were distilled off to recover a solid material. Thesolid material was prepared as a powder by using acetone and hexane, torecover 2-mercapto-4-benzyloxybenzoxazole (143 mg at a yield of 89%).

[0270] To a solution in DMF (3 ml) of the oxazole (135 mg, 0.525 mmol)and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (186 mg, 0.525 mmol)were added potassium carbonate (110 mg, 0.788 mmol) and 18-crown-6 (14mg, 0.053 mmol), and the resulting mixture was stirred at 80° C. for 90minutes. After the reaction solution was diluted with water, the organiclayer was extracted with ether. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (25 g of silica gel; elutionsolvents:hexane:acetone=20:3); the resulting crystal was recrystallizedfrom acetone-hexane, to recover the objective compound of 206 mg (at ayield of 74%) as a colorless crystal.

[0271] The amide (188 mg, 0.354 mmol) was dissolved in trifluoroaceticacid (5 ml) while cooling in ice bath, followed by addition ofthiophenol (440 mg, 3.54 mmol) with stirring for 2 minutes. After thetemperature was then back to ambient temperature, the mixture wasstirred for 12 hours. Furthermore, thiophenol (440 mg, 3.54 mmol) wasadded to the resulting solution, for 24-hr-stirring. Under reducedpressure, the solvents were distilled off. The resulting residue wasdiluted with water and extracted with ethyl acetate. The organic layerwas washed sequentially with saturated sodium hydrogen carbonatesolution, water and saturated sodium chloride solution, and was driedover anhydrous sodium sulfate, from which the solvents were distilledoff. The residue was purified by silica gel column chromatography (75 gof silica gel; elution solvents:hexane:acetone=5:1 to 10:3), and theresulting crystal was recrystallized from acetone-hexane, to recover theobjective compound (108 mg at a yield of 69%) as a colorless crystal.

[0272] Melting Point: 160-161° C.

[0273] IR (KBr) cm⁻¹: 3226, 2963, 1652, 1480, 1036,

[0274] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.50-1.91 (6H, m),2.36 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.33 (2H, t, J=7.1 Hz), 6.72(1H, dd, J=8.1, 1.2 Hz), 6.97 (1H, dd, J=8.1, 1.2 Hz), 7.06 (1H, t,J=8.1 Hz), 7.09 (1H, d, J=8.5 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd,J=8.5, 6.6 Hz) 8.66 (1H, br s), 9.57 (1H, br s).

[0275] EIMS m/z (relative intensity): 440 (M⁺, 100).

[0276] Elementary Analysis: C₂₅H₃₂N₂O₃S Required: C, 68.15; H, 7.32; N,6.36; S, 7.28. Found: C, 68.05; H, 7.33; N, 6.34; S, 7.18.

Example 23

[0277] Production of6-(4-acetyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0278] Acetic anhydride (18 mg, 0.177 mmol) was added to a solution of6-(4-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (52mg, 0.118 mmol) in pyridine (1 ml), with stirring at ambient temperaturefor 12 hours. The reaction solution was diluted with an aqueous 5%potassium hydrogen sulfate solution, was extracted the organic layerwith ether. The organic layer was washed sequentially with an aqueous 5%potassium hydrogen sulfate solution, water and saturated sodium chloridesolution, and was dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (5 g of silica gel; elutionsolvents:hexane:acetone=5:1), and the resulting crystal wasrecrystallized from acetone-hexane, to recover the objective compound(37 mg at a yield of 64%) as a colorless crystal.

[0279] Melting Point: 116-117° C.

[0280] IR (KBr) cm⁻¹: 3436, 3222, 2962, 1772,-1645.

[0281] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.50-1.91 (6H, m),2.32 (3H, s), 2.36 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.34 (2H, t,J=7.1 Hz), 7.08 (1H, dd, J=8.1, 1.0 Hz), 7.09 (1H, d, J=8.6 Hz), 7.09(1H, d, J=6.6 Hz), 7.20 (1H, dd, J=8.6, 6.6 Hz), 7.29 (1H, t, J=8.1 Hz),7.46 (1H, dd, J=8.1, 1.0 Hz), 8.67 (1H, br.s),

[0282] EIMS m/z (relative intensity): 482 (M⁺, 100).

[0283] Elementary Analysis: C₂₇H₃₄N₂O₄S Required: C, 67.19; H, 7.10; N,5.80; S, 6.64. Found: C, 67.19; H, 7.18; N, 5.82; S, 6.55.

Example 24

[0284] Production of6-(4-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0285] p-Toluenesulfonic acid monohydrate (95 mg, 0.5 mmol) was added toa solution of 3-hydroxyanthranilic acid (1.93 g, 12.6 mmol) inhydrochloric acid-saturated methanol (40 ml) solution, for reflux underheating for 12 hours. The solvents were distilled off, and the resultingresidue was diluted with ethyl acetate. The organic layer was washedsequentially with an aqueous potassium hydrogen carbonate solution,water and saturated sodium chloride solution, and was dried overanhydrous sodium sulfate, from which the solvents were distilled off.The residue was dissolved in ether, and then, insoluble matters werefiltered off. The filtrate was concentrated to recover the residue.Triethylamine (1.85 g, 18.25 mmol) was added to a solution of theresidue (1.22 g, 7.37 mmol) in dichloromethane (10 ml), followed bydropwise addition of a solution of thiophosgene (923 mg, 8.03 mmol) indichloromethane (2 ml), for subsequent stirring at ambient temperaturefor 5 minutes. The reaction solution was concentrated, and the resultingresidue was diluted with ethyl acetate. The organic layer was washedsequentially with 1 N hydrochloric acid, water and saturated sodiumchloride solution, and was dried over anhydrous sodium sulfate, fromwhich the solvents were distilled off. The resulting solid matter wascrystallized from ethyl acetate-hexane, to recover4-methoxycarbonyl-2-mercaptobenzoxazole (1.28 g at a yield of 84%). To asolution in DMF (20 ml) of the oxazole (1.05 g, 5.0 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (1.77 g, 5.0 mmol) wereadded potassium carbonate (1.04 g, 7.5 mmol) and 18-crown-6 (132 mg, 0.5mmol), and the resulting mixture was stirred at 80° C. for 2 hours.After the reaction solution was diluted with water, the organic layerwas extracted with ether. The organic layer was washed sequentially withwater and saturated sodium chloride solution, and was dried overanhydrous magnesium sulfate, from which the solvents were distilled off.The residue was purified by silica gel column chromatography (100 g ofsilica gel; elution solvents:hexane:acetone=5:1); the resulting crystalwas recrystallized from acetone-hexane, to recover the objectivecompound of 1.84 g (at a yield of 76%) as a colorless needle-likecrystal.

[0286] Melting Point: 131-132° C.

[0287] IR (KBr) cm⁻¹: 3408, 3221, 3172, 2965, 1713, 1641.

[0288] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.53-1.97 (6H, m),2.39 (2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.40 (2H, t, J=7.2 Hz), 3.91(3H, s), 7.08 (1H, d, J=8.8 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd,J=8.8, 6.6 Hz), 7.34 (1H, t, J=8.1 Hz), 7.74 (1H, dd, J=8.1, 1.2 Hz),7.82 (1H, dd, J=8.1, 1.2 Hz), 8.60 (1H, br s).

[0289] EIMS m/z (relative intensity): 482 (M⁺), 176 (100).

[0290] Elementary Analysis: C₂₇H₃₄N₂O₄S Required: C, 67.19; H, 7.10; N5.80; S, 6.64. Found: C, 67.29; H, 7.21; N, 5.71; S, 6.62.

Example 25

[0291] Production of6-(4-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0292] To a solution in THF (10 ml) of6-(4-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(965 mg, 2.0 mmol) was added t-BuOH (4 ml), followed by addition of asolution of lithium hydroxide monohydrate (336 mg, 8 mmol) in water (4ml), with stirring at ambient temperature for 12 hours. Afterdistillation of the solvents under reduced pressure, the resultingresidue was extracted with ethyl acetate. The organic layer was washedsequentially with 0.5 N hydrochloric acid, water and saturated sodiumchloride solution, and was dried over anhydrous sodium sulfate, fromwhich the solvents were distilled off. The resulting crude crystal wasrecrystallized from acetone-hexane, to recover the objective compound(799 mg at a yield of 85%) as a colorless crystal.

[0293] Melting Point: 174-176° C.

[0294] IR (KBr) cm⁻¹: 3421, 3244, 2963, 1649, 1493.

[0295] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.47-1.88 (6H, m),2.37 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.34 (2H, t, J=7.1 Hz), 7.08(1H, d, J=8.5 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd, J=8.5, 6.6 Hz),7.3 4(1H, t, J=7.9 Hz), 7.74(1H, dd, J=7.9,0.5 Hz), 7.80 (1H, dd,J=7.9,0.5 Hz), 8.76 (1H, br s).

[0296] Elementary Analysis: C₂₃H₃₂N₂O₄S Required: C, 66.64; H, 6.88; N,5.98; S, 6.84. Found: C, 66.36; H, 6.86; N, 6.03; S, 6.64.

Example 26

[0297] Production of6-(4-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0298] To a solution in THF (10 ml) of6-(4-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(613 mg, 1.5 mmol) was added triethylamine (200 mg, 1.98 mmol), followedby gradual addition of methyl chloroformate (195 mg, 1.80 mmol) undercooling in ice bath, with stirring for 30 minutes. The depositedtriethylamine hydrochloride salt was filtered off; to the resultingfiltrate under cooling in ice bath was gradually added an aqueoussuspension (1.5 m) of sodium borohydride (227 mg, 6.0 mmol); and theresulting mixture was stirred for 30 minutes. To the reaction solutionwas added water, to extract the organic layer with ethyl acetate. Theorganic layer was washed sequentially with water and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off. The residue was purified by silica gelcolumn chromatography (25 g of silica gel; elutionsolvents:hexane:acetone=5:2 to 5:3), and the resulting crude crystal wasrecrystallized from acetone-ether-hexane, to recover the objectivecompound (468 mg at a yield of 69%) as a colorless crystal.

[0299] Melting Point: 93-95° C.

[0300] IR (KBr) cm⁻¹: 3358, 3243, 2963, 1646, 1506.

[0301] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.50-1.92 (6H,m),2.37 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.35 (2H, t, J=7.1 Hz), 4.67(1H, t, J=5.5 Hz),4.83 (2H, d, J=5.5 Hz), 7.09 (1H, d, J=8.1 Hz), 7.09(1H, d, J=6.6 Hz), 7.19 (1H, dd, J=8.1, 6.6 Hz), 7.24 (1H, t, J=7.8 Hz),7.37 (1H, dd, J=7.8, 1.4 Hz), 7.40 (1H, dd, J=7.8, 1.4 Hz), 8.66 (1H, brs).

[0302] EIMS m/z (relative intensity): 454 (M⁺), 204 (100).

[0303] Elementary Analysis: C₂₆H₃₄N₂O₃S Required: C, 68.69; H, 7.54; N,6.16; S, 7.05. Found: C, 68.70; H, 7.57; N, 6.15; S, 7.01.

Example 27

[0304] Production of6-[4-(N,N-dimethylaminomethyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0305] To a solution in THF (5 ml) of6-(4-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(182 mg, 0.4 mmol) were added triethylamine (81 mg, 0.8 mmol) and4-dimethylaminopyridine (9.8 mg, 0.08 mmol), followed by dropwiseaddition of methane sulfonylchloride (64 mg, 0.56 mmol) under cooling inice bath with stirring, and the resulting mixture was stirred for 30minutes. The reaction solution was extracted with ethyl acetate; theorganic layer was washed sequentially with 0.5 N hydrochloric acid,water and saturated sodium chloride solution and dried over anhydroussodium sulfate, from which the solvents were distilled off. To asolution in THF (7 ml) of the resulting residue (209 mg) was added anaqueous 40% N,N-dimethylamine solution (180 mg, 1.6 mmol), for refluxunder heating for one hour. After the reaction solution was left tostand and cooled, the reaction solution was extracted with ethylacetate; the organic layer was washed with an aqueous sodium hydrogencarbonate solution, water and saturated sodium chloride solution anddried over anhydrous sodium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (10 g of silica gel; elution solvents:hexane:acetone=5:3,chloroform:ammonia-saturated methanol=19:1), and the resulting crystalwas recrystallized from acetone-hexane, to recover the objectivecompound (137 mg at a yield of 71%) as a colorless crystal.

[0306] Melting Point: 113-115° C.

[0307] IR (KBr) cm⁻¹: 3435, 3237, 2964, 1647, 1506.

[0308] H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.93 (6H,m),2.24 (6H, s), 2.37 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.35 (2H, t,J=7.2 Hz), 3.77 (2H, s), 7.09 (1H, d, J=8.3 Hz), 7.09 (1H, d, J=6.8 Hz),7.19 (1H, dd, J=8.3, 6.8Hz), 7.22 (1H, t, J=7.6 Hz), 7.28 (1H, dd,J=7.6, 1.7 Hz), 7.41 (1H, dd, J=7.6, 1.7 Hz), 8.65 (1H, br s).

[0309] EIMS m/z (relative intensity): 481 (M⁺), 207 (100)

[0310] Elementary Analysis: C₂₈H₃₉N₃O₂S Required: C, 69.82; H, 8.16; N,8.72; S, 6.66. Found: C, 69.76; H, 8.23; N, 8.64; S, 6.72.

Example 28

[0311] Production of6-(4-N,N-dimethylaminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0312] To a solution in THF (50 ml) of 2-amino-3-nitrophenol (1.54 g, 10mmol) was added portions of sodium hydride (528 mg, 22 mmol) undercooling in ice bath, and the resulting mixture was stirred at 60° C. for5 minutes. Then, portions of thiophosgene (1.38 g, 12 mmol) were addedto the mixture, which was then stirred at 60° C. for 5 minutes. Afterdistillation of the solvent, the resulting residue was adjusted toacidity by using 1 N hydrochloric acid; the resulting solid matter wasfiltered and recovered, which was then purified by silica gel columnchromatography (200 g of silica gel; elution solvents: chloroform,chloroform:methanol=100:1 to 50:1), and the resulting solid matter wascrystallized from acetone-hexane, to recover2-mercapto-4-nitrobenzoxazole (807 mg at a yield of 41%) as a yellowcrystal. To a solution in DMF (6 ml) of the resulting oxazole (216 mg,1.1 mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (390 mg, 1.1mmol) were added potassium carbonate (228 mg, 1.65 mmol) and 18-crown-6(29 mg, 0.11 mmol), and the resulting mixture was stirred at 80° C. for2 hours. After the reaction solution was diluted with water, the organiclayer was extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (70 g of silica gel; elution solvents:hexane:acetone=5:1to 10:3); the resulting crystal was recrystallized from acetone-hexane,to recover6-(4-nitrobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (304mg at a yield of 59%) as a pale yellow crystal (melting point of132-133° C.).

[0313] The nitro material (386 mg, 0.822 mmol) was dissolved in aceticacid (8 ml), followed by addition of zinc (1.07 g, 16.44 mmol) undercooling in ice bath, and the resulting mixture was stirred at ambienttemperature for 5 minutes. The reaction solution was diluted with ethylacetate and filtered through celite, which was then adjusted toneutrality by using an aqueous sodium hydrogen carbonate solution. Theorganic layer was washed sequentially with an aqueous sodium hydrogencarbonate solution, water and saturated sodium chloride solution, andwas dried over anhydrous sodium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (38 g of silica gel; elutionsolvents:dichloromethane:hexane:acetone=4:4:1); the resulting crystalwas recrystallized from acetone-hexane, to recover6-(4-aminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (231mg at a yield of 64%) as a pale yellow crystal (melting point of167-168° C.). To a solution of the amine material (273 mg, 0.621 mmol)in acetonitrile (7.5 ml) were sequentially added a solution of anaqueous 37% formaldehyde solution (504 mg, 5.78 mmol) in acetonitrile(7.5 ml) and a suspension of sodium cyanoborohydride (156 mg, 2.48 mmol)in acetonitrile (1 ml); and acetic acid (48 μl) was added to theresulting mixture with stirring at ambient temperature. The resultingmixture was further stirred for 30 minutes as it was. After distillationof the solvents, the resulting residue was diluted with water, andextracted with ethyl acetate. The organic layer was sequentially washedwith water and saturated sodium chloride solution and dried overanhydrous sodium sulfate, from which the solvents were distilled off.The residue was purified by preparative thin layer chromatography(elution solvents:hexane:acetone=5:2); the resulting crystal wasrecrystallized from acetone-hexane, to recover the objective compound(177 mg at a yield of 61%) as a colorless crystal.

[0314] Melting Point: 129-130° C.

[0315] IR (KBr) cm⁻¹: 3435, 3226, 2967, 1645, 1524.

[0316] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=7.1 Hz), 1.51-1.92 (6H, m),2.36 (2H, m), 3.09 (2H, sept, J=7.1 Hz), 3.16 (6H, s), 3.30 (2H, t,J=7.1 Hz), 6.49 (1H, dd, J=8.8, 0.7 Hz), 6.84 (1H, dd, 8.1, 0.7 Hz),7.07 (1H, d, J=8.1 Hz), 7.08 (1H, d, J=8.6 Hz), 7.09 (1H, d, J=6.4 Hz),7.19 (1H, dd, J=8.6, 6.4 Hz), 8.63 (1H, br s).

[0317] EIMS m/z (relative intensity): 467 (M⁺, 100)

[0318] Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N,8.99; S, 6.86. Found: C, 69.42; H, 8.10; N, 8.85; S, 6.77.

Example 29

[0319] Production of6-(5-benzyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0320] To a solution in acetatic acid (21 ml) of4-benzyloxy-2-nitrophenol (1.67 g, 6.8mmol) was added zinc (8.89 g, 136mmol) under cooling in ice bath, with stirring at ambient temperaturefor 2 hours. Zinc was filtered off by using celite; the filtrate wasadjusted to neutrality with sodium hydrogen carbonate, and extractedwith ethyl acetate. The organic layer was sequentially washed with anaqueous sodium hydrogen carbonate solution, water and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off to recover 4-benzyloxy-2-aminophenol(1.40 g at a yield of 95%) as a brown oil. To a solution of theaminophenol (1.4 g, 6.5 mmol) in ethanol (35 ml) was added potassiumo-ethyl dithiocarbonate (1.34 g, 8.36 mmol), for reflux under heatingfor 24 hours. After the reaction solution was left to stand for cooling,the solvents were distilled off; the resulting residue was dissolved inwater and adjusted to acidity by using conc. hydrochloric acid, andextracted with ethyl acetate. The organic layer was washed withsaturated sodium chloride solution and dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The resulting solidmaterial was crystallized from acetone-hexane, to recover2-mercapto-5-benzyloxybenzoxazole (1.27 g at a yield of 71%) as a palepink crystal. To a solution of the oxazole (514 mg, 2.0 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (708 mg, 2.0 mmol) in DMF (5ml) were added potassium carbonate (345 mg, 2.5 mmol) and 18-crown-6 (65mg, 0.24 mmol), and the resulting mixture was stirred at 80° C. for 3hours. After the reaction solution was diluted with water, the organiclayer was extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (50 g of silica gel; elution solvents:hexane:acetone=5:1to 10:3); the resulting crystal was recrystallized from acetone-hexane,to recover the objective compound (734 mg at a yield of 69%) as a palered crystal.

[0321] Melting Point: 102-104° C.

[0322] IR (KBr) cm⁻¹: 3413, 3243, 2964, 1644, 1496.

[0323] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.46-1.92 (6H, m),2.47 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.33 (2H, t, J=7.1 Hz), 5.13(2H, s), 6.94 (1H, dd, J=8.8, 2.4 Hz), 7.08 (1H, d, 8.8 Hz), 7.09 (1H,d, J=6.8 Hz), 7.19 (1H, dd, J=8.8, 6.8 Hz), 7.21 (1H, d, J=2.4 Hz),7.25-7.47 (6H, m), 8.68 (1H, br s).

[0324] EIMS m/z (relative intensity): 530 (M⁺, 100).

[0325] Elementary Analysis: C₃₂H₃₈N₂O₃S Required: C, 72.42; H, 7.22; N,5.28; S, 6.04. Found: C, 72.41; H, 7.24; N, 5.11; S, 5.82.

Example 30

[0326] Production of6-(5-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0327] Under cooling in ice bath,6-(5-benzyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(514 mg, 2.0 mmol) was dissolved in trifluoroacetic acid (20 ml),followed by addition of thioanisole (1.24 g, 10 mmol), with stirring atambient temperature for 12 hours. The solvent was distilled off from thereaction solution; the resulting residue was diluted with water, andextracted with ethyl acetate. The organic layer was washed sequentiallywith a saturated sodium hydrogen carbonate solution and saturated sodiumchloride solution, and was dried over anhydrous magnesium sulfate, fromwhich the solvents were distilled off. The residue was purified bysilica gel column chromatography (30 g of silica gel; elutionsolvents:hexane:acetone=5:1 to 5:2), to recover the objective compound(459 mg at a yield of 97%) as a pale red amorphous.

[0328] IR (KBr) cm⁻¹: 3247, 2963, 1649, 1445, 1153.

[0329] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.48-1.91 (6H, m),2.35 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.31 (2H, t, J=7.1 Hz), 6.70(1H, dd, J=8.8, 2.4 Hz), 6.92 (1H, d, J=2.4 Hz), 7.09 (1H, d, J=8.3 Hz),7.10 (1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz), 7.31 (1H, d, J=8.8Hz), 8.68 (1H, br s), 8.92 (1H, s).

[0330] EIMS m/z (relative intensity): 440 (M⁺, 100).

[0331] Elementary Analysis: C₂₅H₃₂N₂O₃S Required: C, 68.15; H, 7.32; N,6.36; S, 7.28. Found: C, 68.16; H, 7.45; N, 6.26; S, 6.86.

Example 31

[0332] Production of9-(5-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

[0333] To a solution of 2-mercapto-5-benzyloxybenzoxazole (515 mg, 2.0mmol) and 9-bromo-N-(2,6-diisopropylphenyl)nonanamide (793 mg, 2.0 mmol)in DMF (15 ml) were added potassium carbonate (415 mg, 3.0 mmol) and18-crown-6 (53 mg, 0.02 mmol), and the resulting mixture was stirred at80° C. for one hour. After the reaction solution was diluted with water,the organic layer was extracted with ethyl acetate. The organic layerwas washed sequentially with water and saturated sodium chloridesolution, and was dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (75 g of silica gel; elutionsolvents:hexane:acetone=5:1); the resulting crystal was recrystallizedfrom acetone-hexane, to recover the objective compound (990 mg at ayield of 86%) as a colorless crystal.

[0334] Under cooling in ice bath,9-[5-benzyloxybenzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)nonanamide(859 mg, 1.5 mmol) was dissolved in trifluoroacetic acid (40 ml),followed by addition of thiophenol (1.86 g, 15 mmol), with stirring atambient temperature for 24 hours. The solvent was distilled off underreduced pressure; the resulting residue was diluted with water, andextracted with ethyl acetate. The organic layer was washed sequentiallywith saturated sodium hydrogen carbonate solution, water and saturatedsodium chloride solution, and was dried over anhydrous sodium sulfate,from which the solvents were distilled off. The residue was purified bysilica gel column chromatography (85 g of silica gel; elutionsolvents:hexane:acetone=5:1 to 10:3 to 5:2), to recover the objectivecompound (634 mg at a yield of 88%) as a pale pink amorphous.

[0335] IR (KBr) cm⁻¹: 3250, 2929, 1651, 1447, 1154.

[0336] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.37-1.69 (10H, m),1.80 (2H, quint, J=7.2 Hz) 2.34 (2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.30(2H, t, J=7.2 Hz), 6.72 (1H, dd, J=8.8, 2.0 Hz), 6.94 (1H, dd, J=2.0,0.5 Hz), 7.10 (1H, d, J=8.6 Hz), 7.11 (1H, d, J=6.6 Hz), 7.21 (1H, dd,J=8.6, 6.6 Hz), 7.32 (1H, dd, J=8.8, 0.5 Hz) 8.87 (1H, br s), 8.93 (1H,br s).

[0337] EIMS m/z (relative intensity): 482 (M⁺, 100).

[0338] Elementary Analysis: C₂₈H₃₈N₂O₃S Required: C, 69.68; H, 7.93; N,5.80; S, 6.64. Found: C, 69.41; H, 8.12; N, 5.62; S, 6.92.

Example 32

[0339] Production of6-(5-acetylthiobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0340] In the same manner as in Example 22 except for the use of6-(5-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of 6-(4-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed to recover the objective compound as apale red crystal.

[0341] Melting Point: 102-104° C.

[0342] IR (KBr) cm⁻¹: 3247, 2963, 1649, 1445, 1153.

[0343] 1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.51-1.96 (6H, m),2.28 (3H, S), 2.38 (2H, m), 3.11 (2H, sept, J=6.8 Hz), 3.38 (2H, t,J=7.1 Hz), 7.06 (1H, dd, J=8.6, 2.4 Hz), 7.11 (1H, d, J=8.8 Hz), 7.12(1H, d, 7.1 Hz), 7.23 (1H, dd, J=8.8, 7.1 Hz), 7.59 (1H, d, J=8.6 Hz),8.71 (1H, br s).

[0344] EIMS m/z (relative intensity): 482 (M⁺, 100).

[0345] Elementary Analysis: C₂₇H₃₄N₂O₄S Required: C, 67.19; H, 7.10; N,5.80; S, 6.64. Found: C, 67.40; H, 7.20; N, 5.72; S, 6.50.

Example 33

[0346] Production of9-(5-acetyloxythiobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

[0347] In the same manner as in Example 22 except for the use of9-(5-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamideinstead of6-(4-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

[0348] Melting Point: 89-90° C.

[0349] IR (KBr) cm⁻¹: 3433, 3266, 1770, 1649, 1496.

[0350] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.37-1.71 (10H, m),1.82 (2H, quint, J=7.2 Hz), 2.25 (3H, S), 2.33 (2H, m), 3.09 (2H, sept,J=6.8 Hz), 3.32 (2H, t, J=7.2 Hz), 7.01 (1H, dd, J=8.8, 2.4 Hz), 7.08(1H, d, J=8.6 Hz), 7.09 (1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.6, 7.1 Hz),7.33 (1H, dd, J=2.4, 0.5 Hz), 7.52 (1H, dd, J=8.8, 0.5 Hz), 8.61 (1H, brs)

[0351] EIMS m/z (relative intensity): 524 (M⁺, 100).

[0352] Elementary Analysis: C₃₀H₄₀N₂O₄S Required: C, 68.68; H, 7.68; N,5.34; S, 6.11. Found: C, 68.79; H, 7.79; N, 5.31; S, 6.09.

Example 34

[0353] Production of6-(5-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0354] In the same manner as in Example 24 except for the use of3-amino-4-hydroxybenzoic acid instead of 3-hydroxyanthranilic acid,reaction progressed to recover the objective compound as a colorlessneedle-like crystal.

[0355] Melting Point: 104-106° C.

[0356] IR (KBr) cm⁻¹: 3417, 3251, 2960, 1720, 1651.

[0357] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.47-1.95 (6H, m),2.36 (2H,m), 3.07 (2H, sept, J=6.8 Hz), 3.38 (2H, t, J=7.1 Hz), 3.88(3H, S), 7.08 (1H, d, J=8.5 Hz), 7.09 (1H, d, J=7.1 Hz), 7.20 (1H, dd,J=8.5, 7.1 Hz), 7.67 (1H, d, J=8.3 Hz), 7.93 (1H, dd, J=8.5, 2.4 Hz),8.12 (1H, dd, J=2.4 Hz), 8.68 (1H, br s).

[0358] Elementary Analysis: C₂₇H₃₄N₂O₄S Required: C, 67.19; H, 7.10; N,5.80; S, 6.64. Found: C, 67.32; H, 7.11; N, 5.81; S, 6.62.

Example 35

[0359] Production of6-(5-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0360] In the same manner as in Example 25 except for the use of6-(5-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

[0361] Melting Point: 198-200° C.

[0362] IR (KBr) cm⁻¹: 3610, 3236, 2963, 1691, 1646.

[0363] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.53-1.94 (6H, m),2.38 (2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.37 (2H, t, J=7.2 Hz), 7.08(1H, d, J=8.5 Hz),7.09 (1H, d, J=6.6 Hz), 7.19 (1H,dd, J=8.5, 6.6 Hz),7.58 (1H, dd, J=8.5, 0.5 Hz), 7.93 (1H, dd, J=8.5, 1.7 Hz), 8.12 (1H,dd, J=1.7, 0.5 Hz), 8.62 (1H, br s).

[0364] EIMS m/z (relative intensity): 468 (M⁺), 176(100)

[0365] Elementary Analysis: C₂₆H₃₂N₂O₄S Required: C, 66.64; H, 6.88; N,5.98; S, 6.84. Found: C, 66.78; H, 7.00; N, 5.98; S, 6.67.

Example 36

[0366] Production of6-(5-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0367] In the same manner as in Example 26 except for the use of6-(5-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

[0368] Melting Point: 152-153° C.

[0369] IR (KBr) cm⁻¹: 3432, 3222, 2965, 1646, 1491.

[0370] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.50-1.92 (6H,m),2.36 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.34 (2H, t, J=7.1 Hz), 4.59(2H, s), 7.09 (1H, d, J=8.1 Hz), 7.09 (1H, d, J=6.8 Hz), 7.19 (1H, dd,J=8.1 , 6.8Hz), 7.24 (1H, dd, J=8.3, 1.5 Hz), 7.46 (1H, d, J=8.3 Hz),7.52 (1H, d, J=1.5 Hz), 8.67 (1H, br s).

[0371] EIMS m/z (relative intensity): 454 (M⁺), 176 (100)

[0372] Elementary Analysis: C₂₆H₃₄N₂O₃S Required: C, 68.69; H, 7.54; N,6.16; S, 7.05. Found: C, 68.59; H, 7.58; N, 6.12; S, 7.11.

Example 37

[0373] Production of6-[5-(N,N-dimethylaminomethyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0374] In the same manner as in Example 27 except for the use of6-(5-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed to recover the objective compound as acolorless crystal.

[0375] Melting Point: 112-113° C.

[0376] IR (KBr) cm⁻¹: 3429, 3238, 2961, 1652, 1502.

[0377] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.50-1.92(6H,m),2.19 (3H, s), 2.20 (3H, s), 2.36 (2H, m), 3.09 (2H, sept, J=6.8Hz), 3.34 (2H, t, J=7.2 Hz), 3.49 (2H, s), 7.09 (1H, d, J=8.6 Hz), 7.09(1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.6, 7.1 Hz), 7.21 (1H, dd, J=8.6,1.5 Hz), 7.46 (1H, d, J=8.6 Hz), 7.48 (1H, d, J=1.5 Hz), 8.66 (1H, brs).

[0378] EIMS m/z (relative intensity): 481 (M⁺), 207 (100).

[0379] Elementary Analysis: C₂₈H₃₉N₃O₂S Required: C, 69.82; H, 8.16; N,8.72; S, 6.66. Found: C, 69.65; H, 8.18; N, 8.65; S, 6.54.

Example 38

[0380] Production of6-(5-N,N-dimethylaminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0381] To a solution of 2-amino-4-nitrophenol (1.54 g, 10 mmol) inethanol (50 ml) was added potassium o-ethyl dithiocarbonate (1.76 g, 11mmol), at reflux under heating for 12 hours. After the reaction solutionwas left to stand for cooling, the solvents were distilled off underreduced pressure; the resulting residue was adjusted to acidity by using1 N hydrochloric acid, and extracted with ethyl acetate. The organiclayer was washed with saturated sodium chloride solution and dried overanhydrous sodium sulfate, from which the solvents were distilled off.The resulting solid material was crystallized from acetone-hexane, torecover 2-mercapto-5-nitrobenzoxazole (1.90 g at a yield of 97%) as ayellow crystal. To a solution of the oxazole (392 mg, 2.0 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (708 mg, 2.0 mmol) in DMF (5ml) were added potassium carbonate (304 mg, 2.2 mmol) and 18-crown-6 (53mg, 0.2 mmol), and the resulting mixture was stirred at 80° C. for 3hours. After the reaction solution was diluted with water, the organiclayer was extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (50 g of silica gel; elution solvents:hexane:acetone=5:1to 10:3); the resulting crystal was recrystallized from acetone-hexane,to recover6-(5-nitrobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (796mg at a yield of 85%) as a pale yellow crystal (of a melting point of118 to 119° C.). The nitro material (670 mg, 1.42 mmol) was dissolved inacetic acid (15 ml), followed by addition of zinc (1.86 g, 28.5 mmol)under cooling in ice bath, and the resulting mixture was stirred atambient temperature for 2 hours. After the reaction solution wasfiltered through celite, the filtrate was adjusted to neutrality byusing an aqueous saturated sodium hydrogen carbonate solution, andextracted with ethyl acetate. The organic layer was washed sequentiallywith an aqueous sodium hydrogen carbonate solution, water and saturatedsodium chloride solution, and was dried over anhydrous sodium sulfate,from which the solvents were distilled off. The residue was purified bysilica gel column chromatography (12 g of silica gel; elutionsolvents:chloroform:methanol=97:3); the resulting crystal wasrecrystallized from methylene chloride-ether, to recover6-(5-aminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (374mg at a yield of 60%) as a pale yellow crystal (of a melting point of151-152° C.). To a solution of the aniline (220 mg, 0.50 mmol) inacetonitrile (3 ml) were sequentially added an aqueous 37% formaldehydesolution (406 mg, 5.0 mmol) and a suspension of sodium cyanoborohydride(126 mg, 2.0 mmol) in acetonitrile (2 ml), followed by dropwise additionof acetic acid (45 μl) with stirring at ambient temperature; and then,the resulting mixture was further stirred for 30 minutes. Afterdistillation of the solvents, the resulting residue was diluted withwater, and extracted with ethyl acetate. The organic layer wassequentially washed with water and saturated sodium chloride solutionand dried over anhydrous sodium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (10 g of silica gel; elution solvents:hexane:methylenechloride:acetone=4:4:1), and the resulting crystal was recrystallizedfrom ether-hexane, to recover the objective compound (122 mg at a yieldof 52%) as a colorless needle-like crystal.

[0382] Melting Point: 130-132° C.

[0383] IR (KBr) cm⁻¹: 3435, 3227, 2961, 1651, 1494.

[0384] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.47-1.92 (6H, m),2.35 (2H,m), 2.89 (6H, s), 3.08 (2H, sept, J=6.8 Hz), 3.31 (2H, t, J=7.1Hz), 6.71 (1H, dd, J=8.8, 2.4 Hz), 6.87 (1H, d, J=2.4 Hz), 7.08 (1H, d,J=8.3 Hz), 7.09 (1H, d, J=6.8 Hz), 7.19 (1H, dd, J=8.3, 6.8 Hz), 7.33(1H, d, J=8.8 Hz), 8.68 (1H, br s).

[0385] EIMS m/z (relative intensity): 467 (M⁺, 100).

[0386] Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N,8.99; S, 6.82. Found: C, 69.44; H, 7.97; N, 8.94; S, 6.86.

Example 39

[0387] Production of6-(6-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0388] To a solution of 2-mercapto-6-hydroxybenzoxazole (167 mg, 1.0mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (354 mg, 1.0 mmol)in DMF (6 ml) were added potassium carbonate (207 mg, 1.5 mmol) and18-crown-6 (26 mg, 0.01 mmol), and the resulting mixture was stirred at80° C. for 2 hours. After the reaction solution was diluted with water,the organic layer was extracted with ethyl acetate. The organic layerwas washed sequentially with water and saturated sodium chloridesolution, and was dried over anhydrous sodium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (70 g of silica gel; elutionsolvents:hexane:acetone=10:3 to 5:1), to recover the objective compound(347 mg at a yield of 79%) as a pale brown amorphous.

[0389] IR (KBr) cm⁻¹: 3247, 2963, 1652, 1484.

[0390] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.51-1.91 (6H, m),2.37 (2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.28 (2H, t, J=7.2 Hz), 6.75(1H, dd, J=8.5, 2.2 Hz), 6.91 (1H, d, J=2.2 Hz), 7.08 (1H, d, J=8.6 Hz),7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd, J=8.8, 6.6 Hz), 7.31 (1H, d, J=8.5Hz) 8.61 (1H, br s), 9.08 (1H, br s).

[0391] EIMS m/z (relative intensity): 440 (M⁺, 100).

[0392] Elementary Analysis: C₂₅H₃₂N₂O₃S Required: C, 68.15; H, 7.32; N,6.36; S, 7.28. Found: C, 67.93; H, 7.37; N, 6.31; S, 7.03.

Example 40

[0393] Production of6-(6-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0394] In the same manner as in Example 24 except for the use of4-amino-3-hydroxybenzoic acid instead of 3-hydroxyanthranilic acid,reaction progressed to recover the objective compound as a colorlessneedle-like crystal.

[0395] Melting Point: 157-158° C.

[0396] IR (KBr) cm⁻¹: 3412, 3236, 2959, 1714, 1647.

[0397] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.51-1.94 (6H, m),2.37 (2H,m), 3.09 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.2 Hz), 3.88(3H, s), 7.08 (1H, d, J=8.6 Hz), 7.09 (1H, d, J=6.6 Hz), 7.20 (1H, dd,J=8.6, 6.6 Hz), 7.65 (1H, dd, J=8.3, 0.5 Hz), 7.95 (1H, dd, J=8.3, 1.7Hz), 8.09 (1H, dd, J=1.7, 0.5 Hz), 8.67 (1H, br s).

[0398] EIMS m/z (relative intensity): 483 (M⁺+1), 69 (100).

[0399] Elementary Analysis: C₂₇H₃₄N₂O₄S Required: C, 67.19; H, 7.10; N,5.80; S, 6.64. Found: C, 67.35; H, 7.13; N, 5.78; S, 6.47.

Example 41

[0400] Production of6-(6-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0401] In the same manner as in Example 25 except for the use of6-(6-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed to recover the objective compound as acolorless crystal.

[0402] Melting Point: 212-213° C.

[0403] IR (KBr) cm⁻¹: 3216, 2964, 1648, 1491, 1430.

[0404] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.51-1.94 (6H, m),2.37 (2H,m), 3.09 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.1 Hz), 7.08(1H, d, J=8.5 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H,dd, J=8.5, 6.6 Hz),7.62 (1H, dd, J=8.3, 0.4 Hz), 7.94 (1H, dd, J=8.3, 1.5 Hz), 8.06 (1H,dd, J=1.5, 0.4 Hz), 8.65 (1H, br s).

[0405] EIMS m/z (relative intensity): 468 (M⁺), 176 (100).

[0406] Elementary Analysis: C₂₆H₃₂N₂O₄S Required: C, 66.64; H, 6.88; N,5.98; S, 6.84. Found: C, 66.81; H, 7.00; N, 5.96; S, 6.64.

Example 42

[0407] Production of6-(6-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0408] In the same manner as in Example 26 except for the use of6-(6-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

[0409] Melting Point: 93-95° C.

[0410] IR (KBr) cm⁻¹: 3421, 3261, 2964, 1645, 1492.

[0411] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.50-1.92 (6H, m),2.37 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.34 (2H, t, J=7.2 Hz), 4.61(2H, s), 7.09 (1H, d, J=8.6 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd,J=8.6 , 6.6Hz), 7.26 (1H, dd, J=8.1, 1.3 Hz), 7.49 (1H, dd, J=8.1, 0.7Hz), 7.49 (1H, dd, J=1.3, 0.7 Hz), 8.64 (1H, br s).

[0412] EIMS m/z (relative intensity): 454 (M⁺), 69 (100).

[0413] Elementary Analysis: C₂₆H₃₄N₂O₃S Required: C, 68.69; H, 7.54; N,6.16; S, 7.05. Found: C, 68.52; H, 7.50; N, 6.12; S, 7.09.

Example 43

[0414] Production of6-[6-(N,N-dimethylaminomethyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0415] In the same manner as in Example 27 except for the use of6-(6-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed to recover the objective compound as acolorless crystal.

[0416] Melting Point: 82-84° C.

[0417] IR (KBr) cm⁻¹: 3246, 2963, 1652, 1503, 1220.

[0418] H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.46-1.93 (6H, m),2.24 (6H, s), 2.36 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.34 (2H, t,J=7.3 Hz), 3.58 (2H, s), 7.08 (1H, d, J=8.3 Hz), 7.09 (1H, d, J=6.6 Hz),7.20 (1H, dd, J=8.3, 6.6 Hz), 7.25 (1H, dd, J=8.1, 1.2 Hz), 7.49 (1H, d,J=1.2 Hz), 7.51 (1H, d, J=8.1 Hz), 8.66 (1H, br s).

[0419] Elementary Analysis: C₂₈H₃ N₃O₂S.0.5H₂O Required: C, 68.53; H,8.22; N, 8.56; S, 6.53. Found: C, 68.53; H, 8.14; N, 8.44; S, 6.64.

Example 44

[0420] Production of6-(6-N,N-dimethylaminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0421] In the same manner as in Example 28 except for the use of2-amino-6-nitrophenol instead of 2-amino-3-nitrophenol, reactionprogressed to recover the objective compound as a colorless needle-likecrystal.

[0422] Melting Point: 149-150° C.

[0423] IR (KBr) cm⁻¹: 3435, 3231, 2966, 1650, 1100.

[0424] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.48-1.89 (6H, m),2.36 (2H,m), 2.93 (6H, s), 3.09 (2H, sept, J=6.8 Hz), 3.27 (2H, t, J=7.1Hz), 6.73 (1H, dd, J=8.8, 2.4 Hz), 6.85 (1H, d, J=2.4 Hz), 7.09 (1H, d,J=8.8 Hz), 7.09 (1H, d, J=6.8 Hz), 7.19 (1H, dd, J=8.8, 6.8 Hz), 7.35(1H, d, J=8.8 Hz), 8.66 (1H, br s).

[0425] EIMS m/z (relative intensity): 467 (M⁺, 100).

[0426] Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N,8.99; S, 6.86. Found: C, 69.46; H, 8.07; N, 8.90; S, 6.96.

Example 45

[0427] Production of6-(6-methylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0428] To a solution of 2-amino-6-methylphenol (636 mg, 4.57 mmol) inethanol (10 ml) was added potassium o-ethyl dithiocarbonate (801 mg, 5mmol), at reflux under heating for 2 hours. The solvents were distilledoff under reduced pressure; subsequently, the resulting residue wasadjusted to acidity by using 1 N hydrochloric acid, and extracted withethyl acetate. The organic layer was washed with saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off. The resulting crude powder wascrystallized from acetone-hexane, to recover2-mercapto-6-methylbenzoxazole (538 mg at a yield of 65%) as a yellowishbrown crystal. To a solution of the oxazole (453 mg, 2.5 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (885 mg, 2.5 mmol) in DMF (8ml) were added potassium carbonate (387 mg, 2.8 mmol) and 18-crown-6 (66mg, 0.25 mmol), and the resulting mixture was stirred at 80° C. for 3hours. After the reaction solution was diluted with water, the organiclayer was extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (50 g of silica gel; elution solvents:hexane:acetone=5:1to 10:3); the resulting crystal was recrystallized fromacetone-ether-hexane, to recover the objective compound (908 mg at ayield of 82%) as a colorless needle-like crystal.

[0429] Melting Point: 112-114° C.

[0430] IR (KBr) cm⁻¹: 3427, 3230, 2964, 1644, 1502.

[0431] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.46-1.92 (6H, m),2.36 (2H,m), 2.41 (3H, S), 3.05 (2H, sept, J=6.8 Hz), 3.32 (2H, t, J=7.1Hz), 7.08 (1H, d, J=8.8 Hz), 7.09 (1H, d, J=6.6 Hz), 7.12 (1H, dd,J=8.1, 2.4 Hz), 7.20 (1H, dd, J=8.8, 6.6 Hz), 7.36 (1H, dd, J=2.4, 0.7Hz), 7.43 (1H, d, J=8.1 Hz), 8.68 (1H, br s).

[0432] EIMS m/z (relative intensity): 438 (M⁺, 100).

[0433] Elementary Analysis: C₂₆H₃₄N₂O₂S Required: C, 71.20; H, 7.81; N,6.39; S, 7.31. Found: C, 71.08; H, 7.99; N, 6.27; S, 7.04.

Example 46

[0434] Production of6-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0435] To a solution of 3-aminosalicylic acid (1.53 g, 10 mmol) inethanol (70 ml) was added potassium o-ethyl dithiocarbonate (3.2 g, 20mmol), at reflux under heating for 2.5 hours. After the reactionsolution was left to stand for cooling, the solvents were distilled offunder reduced pressure; the resulting residue was adjusted to acidity byusing 1 N hydrochloric acid; the resulting deposited precipitate wasfiltered and dried, to recover 7-carboxyl-2-mercaptobenzoxazole (1.3 gat a yield of 67%) as a brown powder. To a solution of the carboxylicacid (976 mg, 5.0 mmol) in methanol (50 ml) was added p-toluenesulfonicacid monohydrate (95 mg, 0.5 mmol), for reflux under heating for 4 days.After the solution was left to stand for cooling, the solvents weredistilled off under reduced pressure; the resulting residue wasextracted with ethyl acetate. The organic layer was washed sequentiallywith water and saturated sodium chloride solution and dried overanhydrous sodium sulfate, from which the solvents were distilled off.The resulting solid material was crystallized from acetone-hexane, torecover 7-methoxycarbonyl-2-mercaptobenzoxazole (0.955 g at a yield of91%) as a brown powder. To a solution of the oxazole (837 mg, 4.0 mmol)and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (1.42 g, 4.0 mmol) inDMF (20 ml) were added potassium carbonate (608 mg, 4.4 mmol) and18-crown-6 (106 mg, 0.4 mmol), and the resulting mixture was stirred at80° C. for 2 hours. After the reaction solution was diluted with water,the organic layer was extracted with ethyl acetate. The organic layerwas washed sequentially with water and saturated sodium chloridesolution, and was dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (50 g of silica gel; elutionsolvents:hexane:acetone=5:1); the resulting crystal was recrystallizedfrom acetone-ether-hexane, to recover the objective compound (1.93 g ata yield of 100%) as a colorless needle-like crystal.

[0436] Melting Point: 118-119° C.

[0437] IR (KBr) cm⁻¹: 3420, 2963, 1719, 1645, 1507.

[0438] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.56 (2H, quint,J=7.3 Hz), 1.73 (2H, quint, J=7.3 Hz), 1.90 (2H, quint, J=7.3 Hz), 2.37(2H, t, J=7.3 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.3 Hz),3.93 (3H, s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.42 (1H,t, J=7.9 Hz), 7.80 (1H, dd, J=7.5, 0.9 Hz), 7.81 (1H, dd, J=7.9, 0.9Hz), 8.68 (1H, br s).

[0439] EIMS m/z (relative intensity): 482 (M⁺), 176 (100).

[0440] Elementary Analysis: C₂₇H₃₄N₂O₄S Required: C, 67.19; H, 7.10; N,5.80; S, 6.64. Found: C, 67.42; H, 7.21; N, 5.84; S, 6.49.

Example 47

[0441] Production of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0442] In the same manner as in Example 26 except for the use of6-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed to recover the objective compound as acolorless crystal.

[0443] Melting Point: 175-177° C.

[0444] IR (KBr) cm⁻¹: 3241, 2963, 1691, 1647, 1507.

[0445] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.57 (2H, quint,J=7.3 Hz), 1.73 (2H, quint, J=7.3 Hz), 1.89 (2H, quint, J=7.3 Hz), 2.37(2H, t, J=7.3 Hz), 3.08 (2H, sept, J=6.9 Hz), 3.38 (2H, t, J=7.3 Hz),7.09 (2H, d, J=7.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.37 (1H, t, J=7.9 Hz),7.76 (2H, d, J=7.9 Hz), 8.70 (1H, br s).

[0446] Elementary Analysis: C₂₆H₃₂N₂O₄S Required: C, 66.64; H, 6.88; N,5.98; S, 6.84. Found: C, 66.48; H, 6.87; N, 6.06; S, 6.60.

Example 48

[0447] Production of6-[7-hydroxymethylbenzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0448] In the same manner as in Example 26 except for the use of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-carboxylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

[0449] Melting Point: 91-92° C.

[0450] IR (KBr) cm⁻¹: 3394, 2966, 1647, 1485, 1428.

[0451] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.56 (2H, quint,J=7.3 Hz), 1.72 (2H, quint, J=7.3 Hz), 1.87 (2H, quint, J=7.3 Hz), 2.36(2H, t, J=7.3 Hz), 3.08 (2H, sept, J=6.9 Hz), 3.36 (2H, t, J=7.3 Hz),4.75 (2H, s), 4.88 (1H, br s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t,J=7.6 Hz), 7.26 (1H, t, J=7.3 Hz), 7.29 (1H, dd, J=7.3, 1.7 Hz), 7.46(1H, dd, J=7.3, 1.7 Hz), 8.69 (1H, br s).

[0452] Elementary Analysis: C₂₆H₃₄N₂O₃S Required: C, 68.69; H, 7.54; N,6.16; S, 7.05. Found: C, 68.54; H, 7.68; N, 6.26; S, 6.95.

Example 49

[0453] Production of6-[7-(N,N-dimethylaminomethyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0454] In the same manner as in Example 27 except for the use of6-(7-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

[0455] Melting Point: 102-104° C.

[0456] IR (KBr) cm⁻¹: 3426, 3234, 1646, 1530, 1501.

[0457] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.56 (2H, quint,J=7.3 Hz), 1.72 (2H, quint, J=7.3 Hz), 1.87 (2H, quint, J=7.3 Hz), 2.24(6H, s), 2.36 (2H, t, J=7.3 Hz), 3.08 (2H, sept, J=6.9 Hz), 3.35 (2H, t,J=7.3 Hz), 3.71 (2H, s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz),7.23 (1H, dd, J=7.6, 1.3 Hz), 7.27 (1H, t, J=7.6 Hz), 7.48 (1H, dd,J=7.6, 1.3 Hz), 8.69 (1H, br s);

[0458] Elementary Analysis: C₂₈H₃₉N₃O₂S Required: C, 69.82; H, 8.16; N,8.72; S, 6.65. Found: C, 69.88; H, 8.26; N, 8.65; S, 6.66.

Example 50

[0459] Production of6-(7-N,N-dimethylaminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0460] To a solution of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(328 mg, 0.7 mmol) in t-BuOH (6 ml) were sequentially addedtriethylamine (101 mg, 1.0 mmol) and diphenylphosphoryl azide (248 mg,0.9 mmol), at reflux under heating for 1.5 hours. After the resultingsolution was left to stand for cooling, water was added to the solution,which was then adjusted to alkalinity with an aqueous potassiumhydroxide solution, and extracted with ethyl acetate. The organic layerwas washed sequentially with water and saturated sodium chloridesolution, and was dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The resulting residue was purified bysilica gel column chromatography (10 g of silica gel; elution solvents;hexane:acetone=5:1), to recover6-(7-t-butoxycarbonylaminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(171 mg at a yield of 45%) as a colorless needle-like crystal.

[0461] The N-t-butoxycarbonylamino material (150 mg, 0.28 mmol) wasdissolved in trifluoroacetic acid (2 ml), with stirring at ambienttemperature for 2 hours. After distillation of trifluoroacetic acid, anaqueous sodium hydrogen carbonate solution was added to the resultingresidue, and extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The resulting residue was purified by preparative thinlayer chromatography (elution solvents; hexane:acetone=5:3), to recover6-(7-aminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (126mg at a yield of 45%) as a pale brown needle-like crystal. To a solutionof the aniline (180 mg, 0.41 mmol) in acetonitrile (3 ml) was added anaqueous 37% formaldehyde solution (123 mg, 4.1 mmol) under cooling inice bath and was additionally added gradually sodium cyanoborohydride(100 mg, 1.6 mmol), followed by addition of acetic acid (0.05 ml). Tenminutes later, acetic acid (0.05 ml) was additionally added, withstirring for 20 minutes. To the reaction solution was added water, andextracted with ethyl acetate. The organic layer was sequentially washedwith an aqueous sodium hydrogen carbonate solution and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off. The residue was purified by silica gelcolumn chromatography (12 g of silica gel; elutionsolvents:hexane:acetone=5:2), and the resulting crude crystal wasrecrystallized from acetone-hexane, to recover the objective compound(100 mg at a yield of 52%) as a colorless needle-like crystal.

[0462] Melting Point: 129-130° C.

[0463] IR (KBr) cm⁻¹: 3435, 2965, 1645, 1537, 1497.

[0464] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.56 (2H, quint,J=7.3 Hz), 1.71 (2H, quint, J=7.3 Hz), 1.87 (2H, quint, J=7.3 Hz), 2.36(2H, t, J=7.3 Hz), 3.02 (6H, s), 3.08 (2H, sept, J=6.9 Hz), 3.33 (2H, t,J=7.3 Hz), 6.59 (1H, dd, J=8.0, 1.0 Hz), 6.95 (1H, dd, J=8.0, 1.0 Hz),7.09 (2H, d, J=7.6 Hz), 7.12 (1H, t, J=8.0 Hz), 7.19 (1H, t, J=7.6 Hz),8.69 (1H, br s).

[0465] EIMS m/z (relative intensity): 467 (M⁺), 193 (100).

[0466] Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N,8.99; S, 6.86. Found: C, 69.37; H, 8.06; N, 8.87; S, 6.85.

Example 51

[0467] Production of6-[7-(1-morpholino)methylbenzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0468] To a solution of6-(7-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(182 mg, 0.4 mmol) in dichloromethane (4 ml) were added triethylamine(61 m g , 0.6 mmol) and 4- dimethylaminopyridine (5 mg, 0.04 mmol),followed by dropwise addition of methane sulfonylchloride (57 m g , 0.5mmol) under cooling in ice bath with stirring; the temperature wasallowed to warm temperature; and then, the resulting solution wasstirred for 15 minutes. The reaction solution was extracted with ethylacetate; the organic layer was washed sequentially with 0.5 Nhydrochloric acid and saturated sodium chloride solution, and was driedover anhydrous magnesium sulfate, from which the solvents were distilledoff. Morpholine (139 mg, 1.6 mmol) was added to a solution of theresulting residue in THF (4 ml), at reflux under heating for one hour.The reaction solution was extracted with ethyl acetate; the organiclayer was sequentially washed with an aqueous sodium hydrogen carbonatesolution and saturated sodium chloride solution and dried over anhydroussodium sulfate, from which the solvents were distilled off. Theresulting crude crystal was recrystallized from acetone-ether-hexane, torecover the objective compound (170 mg at a yield of 81%) as a colorlessneedle-like crystal.

[0469] Melting Point: 117-118° C.

[0470] IR (KBr) cm⁻¹: 3440, 2963, 1647, 1501, 1428.

[0471] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.56 (2H, quint,J=7.3 Hz), 1.72 (2H, quint, J=7.3 Hz), 1.87 (2H, quint, J=7.3 Hz), 2.36(2H, t, J=7.3 Hz), 2.42-2.45 (4H, m), 3.08 (2H, sept, J=6.9 Hz), 3.35(2H, t, J=7.3 Hz), 3.56-3.59 (4H, m), 3.74 (2H, s), 7.09 (2H, d, J=7.6Hz), 7.19 (1H, t, J=7.6 Hz), 7.24 (1H, dd, J=7.6, 1.9 Hz), 7.27 (1H, t,J=7.6 Hz), 7.48 (1H, dd, J=7.6, 1.9 Hz), 8.70 (1H, br s).

[0472] Elementary Analysis: C₃₀H₄₁N₃O₃S Required: C, 68.80; H, 7.89; N,8.02; S, 6.12. Found: C, 68.72; H, 7.91; N, 7.92; S, 6.23.

Example 52

[0473] Production of6-[7-(tetrazol-5-yl)benzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0474] To a solution of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(469 mg, 1.0 mmol) and 1-hydroxybenzotriazole ammonium salt (167 mg, 1.1mmol) in DMF (8 ml) was added WSC (211 mg, 1.1 mmol), and the resultingmixture was stirred at ambient temperature for 15 hours. After thereaction solution was extracted with ethyl acetate, the organic layerwas washed sequentially with diluted hydrochloric acid, water andsaturated sodium chloride solution, and was dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (30 g of silica gel;elution solvents:chloroform:methanol=5:2), to recover6-(7-carbamoylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(493 mg at a yield of 100%). The amide material (493 mg, 1.0 mmol) wasdissolved in phosphorus oxychloride (3 ml), with stirring at ambienttemperature for 24 hours. The reaction solution was poured into icewater, to decompose excess phosphorus oxychloride; the resultingsolution was neutralized with an aqueous potassium hydroxide solution,and extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous sodium sulfate, from which the solvents weredistilled off. The resulting crude crystal was recrystallized fromacetone-ether-hexane, to recover6-(7-cyanobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (315mg at a yield of 70%). To a solution of the nitrile material (300 mg,0.67 mmol) in DMF (3 ml) were added sodium azide (173.5 mg, 2.67 mmol)and ammonium chloride (142.8 mg, 2.67 mmol), with stirring at 120° C.for 15 hours. To the resulting reaction solution was added 1 Nhydrochloric acid, and resulting mixture was extracted with ethylacetate. The organic layer was washed with water and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off. The resulting residue was purified bysilica gel column chromatography (20 g of silica gel; elutionsolvents:chloroform:acetone:acetic acid=60:4:1). The resulting crystalwas recrystallized from acetone-ether-hexane, to recover the objectivecompound (115 mg at a yield of 35%) as a colorless crystal.

[0475] Melting Point: 218-220° C.

[0476] IR (KBr) cm⁻¹: 3425, 2963, 1647, 1501, 1444.

[0477] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.58 (2H, quint,J=7.3 Hz), 1.73 (2H, quint, J=7.3 Hz), 1.92 (2H, quint, J=7.3 Hz), 2.37(2H, t, J=7.3 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.42 (2H, t, J=7.3 Hz),7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.50 (1H, t, J=7.8 Hz),7.78 (1H, dd, J=7.8, 1.0 Hz), 7.89 (1H, dd, J=7.8, 1.0 Hz), 8.70 (1H, brs).

[0478] Elementary Analysis: C₂₆H₃₂N₆O₂S Required: C, 63.39; H, 6.55; N,17.06; S, 6.51. Found: C, 63.60; H, 6.63; N, 16.85; S, 6.45.

Example 53

[0479] Production of2-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)acetamide

[0480] In the same manner as in Example 46 except for the use of2-bromo-N-(2,6-diisopropylphenyl)acetamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless crystal.

[0481] Melting Point: 186-187° C.

[0482] IR (KBr) cm⁻¹: 3437, 2965, 1733, 1637, 1367.

[0483] 1H-NMR (d₆-DMSO) δ: 1.17 (6H, d, J=6.8 Hz), 1.25 (6H, d, J=6.8Hz), 2.90 (2H, sept, J=6.8 Hz), 3.92 (3H, s), 4.27 (2H, s), 6.89 (1H, t,J=7.8 Hz), 6.95 (1H, dd, J=7.8, 1.8 Hz), 7.28 (2H, d, J=7.8 Hz), 7.42(1H, t, J=7.8 Hz), 7.56 (1H, dd, J=7.8, 1.7 Hz), 10.29 (1H, s).

[0484] Elementary Analysis: C₂₃H₂₆N₂O₄S Required: C, 64.77; H, 6.14; N,6.57; S, 7.52. Found: C, 64.92; H, 6.19; N, 6.65; S, 7.55.

Example 54

[0485] Production of9-(6-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

[0486] In the same manner as in Example 46 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

[0487] Melting Point: 122-124° C.

[0488] IR (KBr) cm⁻¹: 3428, 3242, 2968, 1724, 1649.

[0489] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.34-1.68 (10H, m),1.85 (2H, quint, J=7.1 Hz), 2.32 (2H, m), 3.09 (2H, sept, J=6.8 Hz),3.36 (2H, t, J=7.2 Hz), 3.93 (3H, s), 7.08 (1H, d, J=8.3 Hz), 7.09 (1H,d, J=6.6 Hz), 7.19 (1H, dd, J=8.3, 6.6 Hz), 7.40 (1H, t, J=7.8 Hz), 7.79(1H, dd, J=7.8, 1.2 Hz), 7.81 (1H, dd, J=7.8, 1.2 Hz), 8.62 (1H, br s).

[0490] Elementary Analysis: C₃₀H₄₀N₂O₄S Required: C, 68.67; H, 7.68; N,5.34; S, 6.11. Found: C, 68.78; H, 7.66; N, 5.41; S, 6.07.

Example 55

[0491] Production of N-(2,6-diisopropylphenyl)-N′-[7-(7-methoxycarbonylbenzoxazol-2-ylthio)heptyl]urea

[0492] To a solution of 7-methoxycarbonyl-2-mercaptobenzoxazole (100 mg,0.48 mmol) and N-(2,6-diisopropylphenyl)-N′-(7-bromoheptyl)urea (190 mg,0.48mmol) in DMF (5 ml) were added potassium carbonate (73 mg, 0.53mmol) and 18-crown-6 (13 mg, 0.05 mmol), with stirring at 80° C. for 4hours. The reaction solution was diluted with water, and extracted withethyl acetate. The organic layer was sequentially washed with water andsaturated sodium chloride and dried over anhydrous magnesium sulfate,from which the solvents were distilled off. The resulting crystal wasrecrystallized from chloroform-ethyl acetate-hexane, to recover theobjective compound (184 mg at a yield of 73%) as a colorless crystal.

[0493] Melting Point: 179-181° C.

[0494] IR (KBr) cm⁻¹: 3319, 2931, 1722, 1625, 1509.

[0495] 1H-NMR (d₆-DMSO) δ: 1.05 (12H, d, J=6.8 Hz), 1.25-1.42 (8H, m),1.76 (2H, quint, J=7.3 Hz), 3.00 (2H, dt, J=6.6, 6.1 Hz), 3.11 (2H,sept, J=6.8 Hz), 3.29 (2H, t, J=7.3 Hz), 3.86 (3H, s), 5.48 (1H, br s),6.93 (1H, br s), 7.00 (2H, d, J=7.6 Hz), 7.09 (1H, t, 7.6 Hz), 7.35 (1H,t, J=7.8 Hz), 7.75 (1H, dd, J=7.8, 1.2 Hz), 7.76 (1H, dd, J=7.6, 1.2Hz).

[0496] Elementary Analysis: C₂₉H₃₉N₃O₄S Required: C, 66.26; H, 7.48; N,7.99; S, 6.10. Found: C, 65.99; H, 7.51; N, 8.20; S, 5.94.

Example 56

[0497] Production ofN-(2,6-diisopropylphenyl)-N′-[7-(7-methoxycarbonylbenzoxazol-2-ylsulfinyl)heptyl]urea

[0498] To a solution in dichloromethane-methanol (2:1, 9 ml) of theN-(2,6-diisopropylphenyl)-N′-[7-(7-methoxycarbonylbenzoxazol-2-ylthio)heptyl]urea(100 mg, 0.19 mmol) recovered in Example 55 was added m-chloroperbenzoicacid (60 mg, 0.19 mmol) at 0° C., with stirring at ambient temperaturefor 14 hours. The reaction solution was diluted with an aqueous sodiumhydrogen carbonate solution, and extracted with ethyl acetate. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The resultingresidue was purified by preparative thin layer chromatography (elutionsolvents; chloroform:acetone:methanol=75:25:1); the resulting crystalwas recrystallized from chloroform-ethyl acetate-hexane, to recover theobjective compound (66 mg at a yield of 64%) as a colorless crystal.

[0499] Melting Point: 145-147° C.

[0500] IR (KBr) cm⁻¹: 3319, 2931, 1727, 1626, 1295.

[0501] 1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.28-1.38 (4H, m),1.38-1.51 (4H, 1.70-1.90 (2H, m), 3.06 (2H, dd, J=6.6, 6.1 Hz), 3.19(2H, sept, J=6.8 Hz), 3.38-3.52 (2H, m), 3.98 (3H, s), 5.57 (1H, br s),7.01 (1H, br s), 7.09 (2H, d, J=7.3 Hz), 7.18 (1H, t, J=7.3 Hz), 7.62(1H, t, J=7.9 Hz), 8.06 (1H, dd, J=7.9, 1.2 Hz), 8.14 (1H, dd, J=7.9,1.2 Hz).

[0502] Elementary Analysis: C₂₉H₃₉N₃O₅S Required: C, 64.30; H, 7.26; N,7.76; S, 5.92. Found: C, 64.08; H, 7.53; N, 7.64; S, 5.94.

Example 57

[0503] Production ofN-(2,6-diisopropylphenyl)-N′-[7-(5-N,N-dimethylaminobenzoxazol-2-ylthio)heptyl]urea

[0504] To a solution of 2-mercapto-5-nitrobenzoxazole (200 mg, 1.02mmol) and N-(7-bromoheptyl)-N′-(2,6-diisopropylphenyl)urea (484 mg, 1.02mmol) in DMF (5 ml) were added potassium carbonate (185 mg, 1.34 mmol)and 18-crown-6 (32 mg, 0.10 mmol),with stirring at 80° C. for 4 hours.The reaction solution was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The resultingcrystal was recrystallized from chloroform-ethyl acetate-hexane, torecoverN-(2,6-diisopropylphenyl)-N′-[7-(5-nitrobenzoxazol-2-ylthio)heptyl]urea(500 mg at a yield of 96%) as a pale yellow crystal (at a melting pointof 134-135° C.).

[0505] The nitro material (387 mg, 0.76 mmol) was dissolved in aceticacid (8 ml), followed by addition of zinc (987 mg, 15.1 mmol) undercooling in ice bath, and the resulting mixture was stirred at ambienttemperature for 15 minutes. After the reaction solution was diluted withethyl acetate and filtered through celite, the filtrate was adjusted toneutrality by using an aqueous sodium hydrogen carbonate solution. Theorganic layer was washed sequentially with an aqueous sodium hydrogencarbonate solution, water and saturated sodium chloride solution, andwas dried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (hexane:acetone=2:1); the resulting crystal wasrecrystallized from chloroform-ethyl acetate-ether, to recover N-(2,6-diisopropylphenyl)-N′-[7-(5-aminobenzoxazol-2-ylthio)heptyl]urea (320mg at a yield of 88%) as a pale yellow powdery crystal. To a solution ofthe amine (160 mg, 0.33 mmol) in acetonitrile (3 ml) were sequentiallyadded a solution of an aqueous 37% formaldehyde solution (269 mg, 3.32mmol) in acetonitrile (1 ml) and a suspension of sodium cyanoborohydride(83 mg, 1.33 mmol) in acetonitrile (1 ml), followed by dropwise additionof acetic acid (27 μl) with stirring at ambient temperature; and then,the resulting mixture was further stirred for 30 minutes. Afterdistillation of the solvents, the resulting residue was diluted withwater, and extracted with ethyl acetate. The organic layer wassequentially washed with water and saturated sodium chloride solutionand dried over anhydrous sodium sulfate, from which the solvents weredistilled off. The residue was purified by preparative thin layerchromatography (elution solvents:hexane:acetone=2:1), and the resultingcrystal was recrystallized from acetone-hexane, to recover the objectivecompound (67 mg at a yield of 40%) as a colorless crystal.

[0506] Melting Point: 139-140° C.

[0507] IR (KBr) cm⁻¹: 3321, 2929, 1629, 1571, 1149.

[0508] 1H-NMR (d₆-DMSO) δ: 1.06 (12H, d, J=6.8 Hz), 1.21-1.31 (4H, m),1.33-1.43 (4H, m), 1.71 (2H, quint, J=7.3 Hz), 2.83 (6H, 3.00 (2H, dt,J=6.6, 6.1 Hz), 3.11 (2H, sept, J=6.8 Hz), 3.21 (2H, t, J=7.3Hz), 5.49(1H, br s), 6.65 (1H, dd, J=9.0, 2.7 Hz), 6.81 (1H, d, J=2.7 Hz), 6.93(1H, br s), 7.00 (2H, d, J=8.1 Hz), 7.10 (1H, dd, J=8.1, 6.8 Hz), 7.27(1H, d, J=9.0 Hz).

[0509] Elementary Analysis: C₂₉H₄₂N₄O₂S Required: C, 68.20; H, 8.29; N,10.97; S, 6.28. Found: C, 68.19; H, 8.27; N, 10.73; S, 6.13.

Example 58

[0510] Production of6-(7-methoxycarbonylbenzoxazol-2-ylthiosulfonyl)-N-(2,6-diisopropylphenyl)hexanamide

[0511] To a solution of6-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(37 mg, 0.08 mmol) in methylene chloride (3 ml) was addedm-chloroperbenzoic acid (48 mg, 0.15 mmol) at −20° C., with stirring atambient temperature for 19 hours. The reaction solution was diluted withan aqueous sodium hydrogen carbonate solution, and extracted with ethylacetate. The organic layer was washed with water and dried overanhydrous magnesium sulfate, from which the solvents were distilled off.The resulting residue was purified by preparative thin layerchromatography (elution solvents; chloroform:acetone=4:1); and theresulting crystal was recrystallized from ethyl acetate-hexane, torecover the objective compound (15 mg at a yield of 38%) as a colorlessneedle-like crystal.

[0512] Melting Point: 145-147° C.

[0513] IR (KBr) cm⁻¹: 3235, 2961, 1732, 1652, 1345, 1159.

[0514] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=7.0 Hz), 1.54-1.63 (2H, m),1.66-1.75 (2H, 1.90-1.99 (2H, m), 2.31-2.39 (2H, m), 3.08 (2H, sept,J=7.0 Hz), 3.76 (2H, t, J=7.6 Hz), 3.99 (3H, s), 7.11 (2H, d, J=7.7 Hz),7.21 (1H, t, J=7.7 Hz), 7.70 (1H, t, J=8.1 Hz), 8.17 (1H, dd, J=7.6, 1.2Hz), 8.23 (1H, dd, J=8.1, 1.2 Hz), 8.72 (1H, br s).

[0515] Elementary Analysis: C₂₇H₃₄N₂O₆S.1/6H₂O Required: C, 62.65; H,6.69; N, 5.41; S, 5.92. Found: C, 62.68; H, 6.67; N, 5.47; S, 5.94.

Example 59

[0516] Production of6-[7-(2-N,N-dimethylaminoethyloxycarbonyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0517] A solution of 2,4,6-trichlorobenzoyl chloride (104 mg, 0.425mmol) in THF (2 ml) was dropwise added to a solution of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(199 mg, 0.425 mmol) and tritylamine (52 mg, 0.510 mmol) in THF (1 ml)under cooling in ice bath. After stirring at ambient temperature for 35minutes, the deposited triethylamine hydrochloride salt was filteredoff. From the filtrate was distilled off the solvents under reducedpressure, and a solution of the resulting residue in chloroform (2 ml)was dropwise added to a solution of N,N-dimethyl ethanolamine (38 mg,0.425 mmol), and dimethylaminopyridine (5 mg, 0.043 mmol) in chloroform(1 ml) under cooling in ice bath, with stirring at ambient temperaturefor 40 minutes. After distillation of the solvents from the resultingreaction solution under reduced pressure, the resulting residue wasdiluted with ethyl acetate and water. The organic layer was washedsequentially with saturated sodium hydrogen carbonate solution, waterand saturated sodium chloride solution and dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The resultingresidue was purified by silica gel column chromatography (20 g of silicagel; elution solvents:hexane:acetone=5:2/chloroformmethanol=100:1-20:1-10:1); and the resulting crystal was recrystallizedfrom acetone-hexane, to recover the objective compound (114 mg at ayield of 50%) as a colorless needle-like crystal.

[0518] Melting Point: 119-120° C.

[0519] IR (KBr) cm⁻¹: 3423, 3232, 2966, 1721, 1647.

[0520] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.53-1.96 (6H, m),2.28 (6H,s), 2.37 (2H,m), 2.71 (2H, t, J=5.9 Hz), 3.09 (2H, sept, J=6.8Hz), 3.39 (2H, t, J=7.2 Hz), 4.43 (2H, t, J=5.9 Hz), 7.08 (1H, d, J=8.5Hz), 7.09 (1H, d, J=6.7 Hz), 7.19 (1H, dd, J=8.5, 6.7 Hz), 7.40 (1H, t,J=7.8 Hz), 7.80 (2H, dd, J=7.8, 1.5 Hz), 8.64 (1H, br s).

[0521] Elementary Analysis: C₃₀H₄₁N₃O₄S Required: C, 66.76; H, 7.66; N,7.79; S, 5.94. Found: C, 66.75; H, 7.73; N, 7.80; S, 5.91.

Example 60

[0522] Production of6-[7-(2-N,N-dimethylaminoethyloxycarbamoyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0523] A solution of 2,4,6-trichlorobenzoyl chloride (104 mg, 0.425mmol) in THF (2 ml) was dropwise added to a solution of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(199 mg, 0.425 mmol) and triethylamine (52 mg, 0.510 mmol) in THF (1 ml)under cooling in ice bath. After stirring at ambient temperature for 35minutes, the deposited triethylamine hydrochloride salt was filteredoff. From the filtrate was distilled off the solvents under reducedpressure, and a solution of the resulting residue in chloroform (2 ml)was dropwise added to a solution of N,N-dimethylethylenediamine (44 mg,0.5 mmol) and dimethylaminopyridine (6 mg, 0.005 mmol) in chloroform (1ml) under cooling in ice bath, with stirring at ambient temperature forone hour. After distillation of the solvents under reduced pressure fromthe resulting reaction solution, the resulting residue was diluted withethyl acetate and water. The organic layer was washed sequentially withsaturated sodium hydrogen carbonate solution, water and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off. The resulting residue was purified bysilica gel column chromatography (20 g of silica gel; elutionsolvents:chloroform:saturated ammonia-methanol=20:1); and the resultingcrystal was recrystallized from acetone-hexane, to recover the objectivecompound (60 mg at a yield of 22%) as a colorless crystal.

[0524] Melting Point: 135-137° C.

[0525] IR (KBr) cm⁻¹: 3401, 3255, 2963, 1669, 1648.

[0526] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.94 (6H, m),2.26 (6H, s), 2.37 (2H, m), 2.52 (2H, t, J=6.4 Hz), 3.09 (2H, sept,J=6.8 Hz), 3.40 (2H, t, J=7.1 Hz), 3.46 (2H, q, J=6.4 Hz), 7.09 (1H, d,J=8.3 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H,dd, J=8.3, 6.6 Hz), 7.36(1H, t, J=7.8 Hz), 7.67 (1H, dd, J=7.8, 1.2 Hz), 7.69 (1H, dd, J=7.8,1.2 Hz), 7.74 (1H, br s). 8.66 (1H, br s)

[0527] Elementary Analysis: C₃₀H₄₂N₄O₃S Required: C, 66.88; H, 7.86; N,10.40; S, 6.84. Found: C, 66.71; H, 7.82; N, 10.25; S, 6.67.

Example 61

[0528] Production of2-(7-methoxylcarbonylbenzoxazol-2-ylthio)-N-(2,4,6-trifluorophenyl)acetamide

[0529] In the same manner as in Example 46 except for the use of2-bromo-N-(2,4,6-trichlorophenyl)acetamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

[0530] Melting Point: 190-192° C.

[0531] IR (KBr) cm⁻¹: 3426, 3252, 1723, 1679, 1508.

[0532] 1H-NMR (CDCl₃) δ: 3.99 (3H, s), 4.08 (2H, s), 6.70 (2H, m), 7.41(1H, t, J=7.8 Hz), 7.81 (1H, dd, J=7.8, 1.0 Hz), 7.94 (1H, dd, J=7.8,1.0 Hz), 9.03 (1H, br s).

[0533] Elementary Analysis: C₂₃H₂₆N₂O₄S Required: C, 51.52; H, 2.80; N,7.07; S, 14.38. Found: C, 51.44; H, 2.92; N, 7.03; S, 14.28.

Example 62

[0534] Production of6-(7-methoxylcarbonylbenzoxazol-2-ylthio)-N-(2,4,6-trimethoxyphenyl)hexanamide

[0535] To a solution of 2,4,6-trimethoxyaniline (180 mg, 0.98 mmol) andtriethylamine (111 mg, 1.1 mmol) in chloroform (4 ml) was dropwise added6-bromohexanoyl chloride (214 mg, 1.0 mmol) under cooling in ice bath,with stirring at ambient temperature for one hour. The reaction mixturewas concentrated, and the resulting residue was extracted with ethylacetate. The organic layer was washed with dilute hydrochloric acid, anaqueous sodium hydrogen carbonate solution, water, and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off; the resulting crystal wasrecrystallized from hexane-ether-chloroform, to recover the objectivecompound (320 mg at a yield of 89%) as a colorless needle-like crystal.In the same manner as in Example 46 except for the use of6-bromo-N-(2,4,6-trimethoxyphenyl)hexanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, subsequently, reactionprogressed to recover the objective compound as a colorless needle-likecrystal.

[0536] Melting Point: 136-138° C.

[0537] IR (KBr) cm⁻¹: 3251, 2935, 1727, 1660, 1507.

[0538] 1H-NMR (d₆-DMSO) δ: 1.52 (2H, quint, J=7.3 Hz), 1.64 (2H, quint,J=7.3 Hz), 1.85 (2H, quint, J=7.3 Hz), 2.19 (2H, t, J=7.3 Hz), 3.36 (2H,t, J=7.3 Hz), 3.71 (6H, s), 3.76 (3H, S), 3.93 (3H, s), 6.22 (2H, s),7.42 (1H, t, J=7.8 Hz), 7.80 (1H, dd, J=7.8, 1.2 Hz),7.84 (1H, dd,J=7.8, 1.2 Hz), 7.92 (1H, br S).

[0539] Elementary Analysis: C₂₄H₂₈N₂O₇S Required: C, 59.00; H, 5.78; N,5.73; S, 6.56. Found: c, 58.94; H, 5.82; N, 5.74; S, 6.55

Example 63

[0540] Production of6-(5-methoxycarbonylbenzimidazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0541] To a solution of 5-methoxycarbonyl-2-mercaptobenzimidazole (100mg, 0.48 mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (170 mg,0.48 mmol) in DMF (4 ml) were added potassium carbonate (73 mg, 0.53mmol) and 18-crown-6 (13mg, 0.05 mmol),with stirring at 80° C. for 4hours. The reaction solution was diluted with water, and extracted withethyl acetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The resultingcrystal was purified by preparative thin layer chromatography (elutionsolvents:chloroform:acetone saturated ammonia methanol=80:20:1); and theresulting crystal was recrystallized from ethyl acetate-hexane, torecover the objective compound (137 mg at a yield of 59%) as a colorlesscrystal.

[0542] Melting Point: 190-192° C.

[0543] IR (KBr) cm⁻¹: 3178, 2962, 1716, 1655, 1434, 1297.

[0544] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.51-1.62 (2H, m),1.68-1.77 (2H, m), 1.77-1.87 (2H, m), 2.33-2.41 (2H, m), 3.10 (2H, sept,J=6.8 Hz), 3.35 (2H, t, J=7.2 Hz), 3.87 (3H, s), 7.10 (1H, d, J=8.1 Hz),7.11 (1H, d, J=7.3 Hz), 7.21 (1H, dd, J=8.1, 7.3 Hz), 7.47 (1H, d, J=8.3Hz), 7.77 (1H, dd, J=8.3, 1.6 Hz), 8.03 (1H, br s), 8.71 (1H, br s).

[0545] Elementary Analysis: C₂₇H₃₅N₃O₃S.0.4H₂O Required: C, 66.34; H,7.38; N, 8.60; S, 6.56. Found: C, 66.25; H, 7.37; N, 8.42; S, 6.40.

Example 64

[0546] Production of6-(5-N,N-dimethylaminobenzimidazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0547] To a solution of 2-mercapto-5-nitrobenzimidazole (195 mg, 1.0mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (354 mg, 1.0 mmol)in DMF (7 ml) were added potassium carbonate (152 mg, 1.1 mmol) and18-crown-6 (26 mg, 0.1 mmol),with stirring at 80° C. for 3 hours. Thereaction solution was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off, to recover6-(5-nitrobenzimidazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(600 mg) as a pale yellow oil. The nitro material (640 mg, 1.37 mmol)was dissolved in acetic acid (10 ml), followed by addition of zinc (1.79g, 27.3 mmol) under cooling in ice bath, with stirring at ambienttemperature for 15 minutes. The reaction solution was filtered throughcelite; the resulting filtrate was adjusted to neutrality by using anaqueous sodium hydrogen carbonate solution, and extracted with ethylacetate. The organic layer was washed sequentially with an aqueoussodium hydrogen carbonate solution, water and saturated sodium chloridesolution and dried over anhydrous sodium sulfate solution, from whichthe solvents were distilled off. The residue was purified by silica gelcolumn chromatography (elution solvents; chloroform:methanol=10:1), torecover6-(5-aminobenzimidazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(451 mg at a yield of 75%) as a pale yellow oil.

[0548] To a solution of the aniline (398 mg, 0.91 mmol) in acetonitrile(7 ml) were added sequentially an aqueous 37% formaldehyde solution (736mg, 9.07 mmol) and a suspension of sodium cyanoborohydride (228 mg, 3.63mmol) in acetonitrile (7 ml), followed by dropwise addition of aceticacid (73 μl) while the resulting mixture was stirred at ambienttemperature; and then, the resulting mixture was further stirred for 30minutes. After distillation of the solvents, the resulting residue wasdiluted with water, and extracted with ethyl acetate. The organic layerwas sequentially washed with water and saturated sodium chloridesolution and dried over anhydrous sodium sulfate, from which thesolvents were distilled off. The residue was purified by preparativethin layer chromatography (elution solvents:chloroform:saturated ammoniamethanol=10:1), and the resulting crystal was recrystallized fromchloroform-ethyl acetate-hexane, to recover the objective compound (53mg at a yield of 13%) as a pale brown powdery crystal.

[0549] Melting Point: 109-111° C.

[0550] IR (KBr) cm⁻¹: 3235, 2962, 1651, 1519, 1440.

[0551] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.51-1.59 (2H, m),1.66-1.82 (4H, m), 2.32-2.40 (2H, m), 2.89 (6H, s), 3.10 (2H, sept,J=6.8 Hz), 3.24 (2H, t, J=7.1 Hz), 6.68-6.76 (2H, m), 7.11 (2H, d, J=7.6Hz), 7.18-7.28 (2H, m), 8.71 (1H, br s).

[0552] Elementary Analysis: C₂₇H₃₈N₄OS Required: C, 69.49; H, 8.21; N,12.01; S, 6.87. Found: C, 69.31; H, 8.20; N, 11.90;. S, 6.91.

Example 65

[0553] Production of6-(6-N,N-dimethylaminobenzothiazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0554] To a solution of 2-mercapto-6-nitrobenzothiazole (212 mg, 1.0mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (354 mg, 1.0 mmol)in DMF (6 ml) were added potassium carbonate (152 mg, 1.1 mmol) and18-crown-6 (26 mg, 0.1 mmol),with stirring at 80° C. for 2 hours. Thereaction solution was diluted with water and ethyl acetate. The organiclayer was sequentially washed with an aqueous sodium hydrogen carbonatesolution, water, dilute hydrochloric acid and saturated sodium chloridesolution and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (50 g of silica gel; elutionsolvents:hexane:acetone=5:2), to recover6-(6-nitrobenzothiazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(490 mg at a yield of 100%) as a pale yellow oil. The nitro material(490 mg, 1.0 mmol) was dissolved in acetic acid (5 ml), followed byaddition of zinc (1.3 g, 20 mmol) under cooling in ice bath, withstirring at ambient temperature for 20 minutes. The reaction solutionwas diluted with ethyl acetate and filtered through celite; the filtratewas adjusted to neutrality by using an aqueous sodium hydrogen carbonatesolution. The organic layer was sequentially washed with an aqueoussodium hydrogen carbonate solution, water and saturated sodium chloridesolution and dried over anhydrous sodium sulfate, from which thesolvents were distilled off, to recover6-(6-aminobenzothiazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(426 mg). To a solution of the amine material (380 mg, 0.83 mmol) inacetonitrile (4 ml) were added sequentially an aqueous 37% formaldehydesolution (325 mg, 4.0 mmol) and sodium cyanoborohydride (100.5 mg, 1.6mmol), followed by dropwise addition of acetic acid (0.1 ml) while theresulting mixture was stirred at ambient temperature; and then, theresulting mixture was further stirred for 2 hours as it was.Additionally, acetic acid (0.1 ml) was dropwise added to the mixture,which was stirred for 30 minutes. After distillation of the solventsunder reduced pressure, the resulting residue was diluted with ethylacetate and water. The organic layer was sequentially washed with anaqueous sodium hydrogen carbonate solution, water and saturated sodiumchloride solution and dried over anhydrous magnesium sulfate, from whichthe solvents were distilled off. The residue was purified by silica gelcolumn chromatography (elution solvents:hexane:acetone=10:1 to 5:1), andthe resulting crystal was recrystallized fromacetone-dichloromethane-hexane, to recover the objective compound (152mg at a yield of 38%) as a colorless needle-like crystal.

[0555] Melting Point: 146-147° C.

[0556] IR (KBr) cm⁻¹: 3427, 3233, 1648, 1602, 1460.

[0557] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.50-1.60 (6H, m),1.68-1.75 (2H, m), 1.78-1.85 (2H, m), 2.35 (2H, t, J=6.8 Hz), 2.94 (6H,s), 3.08 (2H, sept, J=6.8 Hz), 3.29 (2H, t, J=7.3 Hz), 6.90 (1H, dd,J=9.0, 2.6 Hz), 7.09 (1H, d, J=7.6 Hz), 7.17 (1H, d, J=2.6 Hz), 7.20(1H, t, J=7.6 Hz), 7.62 (1H, d, J=9.0 Hz), 8.70 (1H, br s).

[0558] Elementary Analysis: C₂₇H₃₇N₃OS₂ Required: C, 67.04; H, 7.71; N,8.69; S, 13.26. Found: C, 67.00; H, 7.83; N, 8.70; S, 13.19.

Example 66

[0559] Production of 6-[(±)-3a,7a-trans-3a,4,5,6,7,7a-hexahydrobenzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0560] A mixture solution of (±)-trans-2-aminocyclohexanol (500 mg, 4.34mmol), carbon disulfide (1 ml) and an aqueous 0.5 N sodium hydroxidesolution (1 ml) was refluxed under heating for 4 hours. The reactionsolution was extracted with ether and then isolated; to the aqueouslayer was added acetic acid to adjust the layer to acidity, and theresulting mixture was extracted with ether. The organic layer was washedwith water and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off.

[0561] To a solution of the resulting(±)-2-mercapto-3a,7a-trans-3a,4,5,6,7,7a-hexahydrobenzoxazole (67 mg,0.43 mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (151 mg, 0.43mmol) in DMF (3 ml) were added potassium carbonate (65 mg, 0.47 mmol)and 18-crown-6 (11 mg, 0.04 mmol), with stirring at 80° C. for 6 hours.The reaction solution was diluted with water, and extracted with ethylacetate. The organic layer was washed with water and dried overanhydrous magnesium sulfate, from which the solvents were distilled off.The residue was purified by preparative thin layer chromatography(elution solvents:hexane:acetone=3:1); and the resulting crystal wasrecrystallized from ethyl acetate-hexane, to recover the objectivecompound (53 mg at a yield of 29%) as a colorless needle-like crystal.

[0562] Melting Point: 121-123° C.

[0563] IR (KBr) cm⁻¹: 3242, 2961, 1652, 1570, 1525.

[0564] 1H-NMR (d₆-DMSO) δ: 1.15 (12H, d, J=6.8 Hz), 1.28-1.87 (12H, m),2.15-2.27 (2H, m), 2.30-2.40 (2H, m), 2.95-3.05 (1H, m), 3.01 (2H, t,J=7.1 Hz), 3.11 (2H, sept, J=6.8 Hz), 3.66 (1H, dt, J=11.5 ,3.8 Hz),7.12 (1H, d, J=8.6 Hz), 7.12 (1H, d, J=6.8 Hz), 7.22 (1H, dd, J=8.6, 6.8Hz), 8.70 (1H, br s).

[0565] EIMS m/z (relative intensity): 430 (M⁺), 204 (100).

[0566] Elementary Analysis: C₂₆H₃₈N₂O₂ S Required: C, 69.73; H, 8.89; N,6.50. Found: C, 69.56; H, 9.00; N, 6.30.

Example 67

[0567] Production of 6-[(±)3a,7a-cis-3a,4,5,6,7,7a-hexahydrobenzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0568] In the same manner as in Example 66 except for the use of(±)-cis-2-aminocyclohexanol instead of (±)-trans-2-aminocyclohexanol,reaction progressed to recover (±)-2-mercapto-3a,7a-cis-3a,4,5,6,7,7a-hexahydrobenzoxazole; subsequently, in the samemanner by using 6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reactionprogressed, to recover the objective compound as a colorless needle-likecrystal.

[0569] Melting Point: 96-97° C.

[0570] IR (KBr) cm⁻¹: 3253, 2964, 2939, 1647, 1592.

[0571] 1H-NMR (d₆-DMSO) δ: 1.15 (12H, d, J=6.8 Hz), 1.32-1.83 (14H, m),2.36 (2H, m), 3.02 (2H, t, J=7.3 Hz), 3.11 (2H, sept, J=6.8 Hz), 3.97(1H, dt, J=8.1, 5.6 Hz), 4.65 (1H, d t, J=8.1, 5.3 Hz), 7.12 (1H, d,J=8.6 Hz), 7.12 (1H, d, J=6.8 Hz), 7.23 (1H, dd, J=8.6, 6.8 Hz), 8.71(1H, br s).

[0572] EIMS m/z (relative intensity): 430 (M⁺), 204 (100).

[0573] Elementary Analysis: C₂₅H₃₈N₂O₂S Required: C, 69.73; H, 8.89; N,6.50; S, 7.44. Found: C, 69.51; H, 8.90; N, 6.35; S, 7.62

Example 68

[0574] Production of6-(imidazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0575] To a solution of 2-mercaptoimidazole (56 mg, 0.56 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (198 mg, 0.56 mmol) in DMF(4 ml) were added potassium carbonate (85 mg, 0.62 mmol) and 18-crown-6(15 mg, 0.06 mmol), with stirring at 80° C. for 6 hours. The reactionsolution was diluted with water, and extracted with ethyl acetate. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The residue waspurified by preparative thin layer chromatography (elutionsolvents:chloroform:methanol=20:1); and the resulting crystal wasrecrystallized from methanol-ethyl acetate-hexane, to recover theobjective compound (76 mg at a yield of 36%) as a colorless needle-likecrystal.

[0576] Melting Point: 190-191° C.

[0577] IR (KBr) cm⁻¹: 3235, 2960, 1644, 1530, 1093.

[0578] 1H-NMR (dB-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.45-1.60 (2H, m),1.63-1.77 (4H, m), 2.30-2.40 (3H, m), 3.05 (2H, t, J=7.3 Hz), 3.10 (2H,sept, J=6.8 Hz), 7.00-7.09 (2H, m), 7.12 (1H, d, J=7.1 Hz), 7.12 (1H, d,J=6.6 Hz), 7.22 (1H, dd, J=7.1, 6.6 Hz), 8.70 (1H, br s).

[0579] EIMS m/z (relative intensity): 373 (M⁺, 100).

[0580] Elementary Analysis: C₂₁H₃₁N₃OS Required: C, 67.52; H, 8.36; N,11.25; S, 8.58. Found: C, 67.39; H, 8.34; N, 11.11; S, 8.35.

Example 69

[0581] Production of6-naphtho[2,3-d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0582] To a solution of 3-amino-2-naphthol (1.59 g, 10 mmol) in ethanol(50 ml) was added potassium o-ethyl dithiocarbonate (3.21 g, 20 mmol),at reflux under heating for 24 hours. After the solvents were distilledoff under reduced pressure, the resulting residue was diluted with waterand adjusted to acidity by using conc. hydrochloric acid, and extractedwith ethyl acetate. The organic layer was washed with saturated sodiumchloride solution and dried over anhydrous sodium sulfate. After thesolvents were distilled off, the resulting residue was purified bysilica gel column chromatography (200 g of silica gel; elution solvents;hexane:acetone=5:1 to 5:2); the resulting crystal was recrystallizedfrom acetone-hexane, to recover 2-mercaptonaphtho[2,3-d]oxazole (1.28 gat a yield of 64%) as a pale brown crystal.

[0583] To a solution of the oxazole (102 mg, 0.5 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (177 mg, 0.5 mmol) in DMF (3ml) were added potassium carbonate (104 mg, 0.75 mmol) and 18-crown-6(13 mg, 0.05 mmol), with stirring at 80° C. for 2 hours. The reactionsolution was diluted with water and extracted with ether. The organiclayer was washed sequentially with water and saturated sodium chloridesolution and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (25 g of silica gel; elutionsolvents:hexane:acetone=5:1); the resulting crystal was recrystallizedfrom acetone-hexane, to recover the objective compound (161 mg at ayield of 68%) as a colorless crystal.

[0584] Melting Point: 159-160° C.

[0585] IR (KBr) cm⁻¹: 3425, 3230, 2964, 1647, 1516.

[0586] 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.54-1.97 (6H, m),2.38 (2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.42 (2H, t, J=7.2 Hz), 7.09(1H, d, J=8.8 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd, J=8.8, 6.6 Hz),7.41-7.50 (2H, m), 7.93-8.03 (4H, m), 8.67 (1H, br s),

[0587] EIMS m/z (relative intensity): 474 (M⁺, 100).

[0588] Elementary Analysis: C₂₉H₃₄N₂O₂S Required: C, 73.38; H, 7.22; N,5.90; S, 6.75. Found: C, 73.38; H, 7.26; N, 5.85; S, 6.65.

Example 70

[0589] Production of6-(5-dimethylphenylsilylmethyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0590] To a solution of6-(5-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(118 mg, 0.27 mmol) in DMF (1 ml) were sequentially added 18-crown-6(7.1 mg, 0.027 mmol), potassium carbonate (56 mg, 0.40 mmol) andchloromethyldimethylphenylsilane (50 mg, 0.27 mmol), with stirring at80° C. for 4 hours. To the reaction solution was again addedchloromethyldimethylphenylsilane (25 mg, 0.13 mmol), with stirring at80° C. for 3 hours. Still additionally, chloromethyldimethylphenylsilane(25 mg, 0.13 mmol) was added, with stirring at 80° C. for 90 minutes.The reaction mixture was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (20 g of silica gel;elution solvents:hexane:acetone=5:1), to recover the objective compound(108 mg at a yield of 68%) as a colorless needle-like crystal.

[0591] Melting Point: 106-108° C.

[0592] IR (KBr) cm⁻¹: 3433, 3222, 2962, 1648, 1472.

[0593] 1H-NMR (d₆-DMSO) δ: 0.38 (6H, s), 1.12 (12H, d, J=6.8 Hz)1.50-1.91 (6H, m), 2.34-2.39 (2H, m), 3.09 (2H, sept., J=6.8 Hz), 3.32(2H, t, J=7.1 Hz), 3.91 (2H, s), 6.87 (1H, dd, J=8.8, 2.5 Hz), 7.08 (1H,d, J=8.3 Hz), 7.09 (1H, d, J=6.8 Hz), 7.16 (1H, d, J=2.5 Hz), 7.19 (1H,dd, J=8.3, 6.8 Hz), 7.32-7.39 (4H, m), 7.56-7.62 (2H, m), 8.65 (1H, brs)

[0594] EIMS m/z (relative intensity): 558 (M⁺, 100).

[0595] Elementary Analysis: C₃₄H₄₄N₂O₃SSi Required: C, 69.35; H, 7.53;N, 4.76; S, 5.45. Found: C, 69.26; H, 7.55; N, 4.76; S, 5.44.

Example 71

[0596] Production ofN-(2,6-diisopropylphenyl)-N′-heptyl-N′-[6-(7-methoxycarbonylbenzoxazol-2-ylthio)hexyl]urea

[0597] 6-Hexanolactone (2.28 g, 20 mmol) and heptylamine (2.42 g, 21mmol) were stirred together at 100° C. for 2 hours. The reaction mixturewas diluted with water, and extracted with ethyl acetate; the organiclayer was washed with 1 N hydrochloric acid, water, an aqueous saturatedsodium hydrogen carbonate solution and saturated sodium chloridesolution and dried over anhydrous sodium sulfate. After the solventswere distilled off, the resulting residue was purified by silica gelcolumn chromatography (150 g of silica gel; elutionsolvents:hexane:acetone=5:2 to 5:3), to recover6-hydroxy-N-heptylhexanamide (2.1 g at a yield of 46%) as a colorlessneedle-like crystal (m.p.: 56-58° C.).

[0598] To a solution of the amide (2.6 g, 11 mmol) in THF (40 ml) withstirring under cooling in ice bath was added lithium aluminium hydride(1.1 g, 30 mmol) under argon atomospher, with stirring at roomtemperature for one hour, at 80° C. for 2 hours and at 90° C. for onehour. The resulting mixture was diluted with ether (300 ml), followed byaddition of several droplets of an aqueous ammonium chloride solution,with stirring at room temperature for 30 minutes. Insoluble matters werefiltered off through celite; the filtrate was concentrated; and theresidue was extracted with diluted hydrochloric acid. The aqueous layerwas washed with ether and ethyl acetate, and was then adjusted toalkalinity by using potassium carbonate, and extracted with chloroformextraction. The organic layer was washed with saturated sodium chloridesolution and dried over potassium carbonate, from which the solventswere distilled off. The resulting solid material was crystallized inacetone-ether-hexane, to recover 6-heptylamino-1-hexanol (1.42 g at ayield of 59%) as a colorless needle-like crystal (m.p.: 50 to 52° C.).

[0599] To a solution of the aminoalcohol (646 mg, 3.0 mmol) inchloroform (4 ml) was dropwise added 2,6-diisopropylphenylisocyanate(610 mg, 3.0 mmol) under cooling in ice bath water, with stirring atambient temperature for 2 hours. To the resulting reaction mixture wasadded hexane, to deposit crystal, which was then filtered and recoveredas N-(2,6-diisopropylphenyl)-N′-heptyl-N′-(6-hydroxyhexyl)urea (1.09 gat a yield of 87%) as a colorless needle-like crystal (m.p.: 137-139°C.).

[0600] To a solution of the urea (419 mg, 1.0 mmol) and4-dimethylaminopyridine (12 mg, 0.1 mmol) in THF (5 ml) were addedtriethylamine (142 mg, 1.4 mmol) and methanesulfonyl chloride (137 mg,1.2 mmol) under cooling in ice bath, and the resulting mixture wasstirred at the temperature for 2 hours. After insoluble matters werefiltered off, the resulting solution was concentrated. The residue wasextracted with ethyl acetate; the organic layer was washed with waterand saturated sodium chloride solution and dried over sodium sulfate,from which the solvents were distilled off. The resulting solid matterwas crystallized in hexane-ethyl acetate, to recover6-[3-(2,6-diisopropylphenyl)-1-heptylureido]hexyl methanesulfonate (433mg at a yield of 87%) as a colorless needle-like crystal (m.p.: 140-141°C.).

[0601] A solution of the methanesulfonate (199 mg, 0.4 mmol) in DMF (2ml) was added to a solution of 7-methoxycarbonyl-2-mercaptobenzoxazole(84 mg, 0.4 mmol), potassium carbonate (83 mg, 0.6 mmol) and 18-crown-6(11 mg, 0.04 mmol) in DMF (1 ml), with stirring at 80° C. for 90minutes. The reaction solution was diluted with water, and extractedwith ethyl acetate. The organic layer was washed sequentially with waterand saturated sodium chloride solution and dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (25 g of silica gel;elution solvents:hexane:acetone=20:1 to 5:1), to recover the objectivecompound (131 mg at a yield of 54%) as a colorless needle-like crystal.

[0602] Melting Point: 120-121° C.

[0603] IR (KBr) cm⁻¹: 3425, 3328, 1728, 1624, 1507.

[0604] 1H-NMR (d₆-DMSO) δ: 0.86 (3H, t, J=6.8 Hz), 1.11 (12H, d, J=6.8Hz) 1.26-1.31 (8H, m), 1.37-1.42 (2H, m), 1.47-1.60 (6H, m), 1.81-1.88(2H, m), 3.14 (2H, sept, J=6.8 Hz), 3.25-3.31 (2H, m), 3.36 (1H, t,J=7.1 Hz), 3.93 (3H, s) 7.04 (1H, br s), 7.05 (2H, d, J=7.8 Hz), 7.15(1H, t, J=7.8 Hz), 7.41 (1H, m), 7.78-7.84 (2H, m)

[0605] EIMS m/z (relative intensity): 609 (M⁺), 189 (100)

[0606] Elementary Analysis: C₃₅H₅₁N₃O₄S Required: C, 68.93; H, 8.43; N,6.89; S, 5.26. Found: C, 69.09; H, 8.50; N, 6.84; S, 5.10.

Example 72

[0607] Production ofN-(2,6-diisopropylphenyl)-N′-heptyl-N′-[6-(oxazolo[4,5-b]pyridin-2-ylthio)hexyl]urea

[0608] In the same manner as in Example 71 except for the use of2-mercaptooxazolo[4,5-b]pyridine instead of7-methoxycarbonyl-2-mercaptobenzoxazole, reaction progressed to recoverthe objective compound as a colorless needle-like crystal.

[0609] Melting Point: 124-125° C.

[0610] IR (KBr) cm⁻¹: 3420, 3328, 1624, 1507, 1402

[0611] 1H-NMR (d₆-DMSO) δ: 0.86 (3H, t, J=7.0 Hz), 1.11 (2.4H, d, J=6.8Hz), 1.11 (9.6H, d, J=6.8 Hz), 1.26-1.32 (8H, m), 1.37-1.43 (2H, m),1.47-1.60 (6H, m), 1.81-1.93 (2H, m), 3.10-3.19 (2H, m), 3.25-3.31 (2H,m), 3.38 (1.6H, t, J=7.2 Hz), 4.22 (0.4H, t, J=7.2 Hz), 7.05 (1H, d,J=8.3 Hz), 7.06 (1H, br s), 7.06 (1H, d, J=6.8 Hz), 7.15 (1H, dd, J=8.3,6.8 Hz), 7.28 (0.8H, dd, J=8.3, 4.9 Hz), 7.30 (0.2H, dd, J=8.3, 4.9 Hz),7.84 (0.2H, dd, J=8.3, 1.5 Hz), 7.95 (0.8H, dd, J=8.3, 1.5 Hz), 8.28(0.2H, dd, J=4.9, 1.5 Hz), 8.39 (0.8H, dd, J=4.9, 1.5 Hz).

[0612] EIMS m/z (relative intensity): 552 (M⁺), 188 (100)

[0613] Elementary Analysis: C₃₂H₄₈N₄O₂S Required: C, 69.53; H, 8.75; N,10.13; S, 5.80. Found: C, 69.65; H, 8.83; N, 10.09; S, 5.86.

Example 73

[0614] Production of2-(7-trifluoromethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)acetamide

[0615] In the same manner as in Example 11 except for the use of2-nitro-6-trifluoromethylphenol instead of3-hydroxy-6-methyl-nitropyridine, reaction progressed to recover2-mercapto-7-trifluoromethylbenzoxazole (110 mg, 0.5 mmol); to asolution of the 2-mercapto-7-trifluoromethylbenzoxazole (110 mg, 0.5mmol) and 2-bromo-N-(2,6-diisopropylphenyl)acetamide (149 mg, 0.5 mmol)was added potassium carbonate (76 mg, 0.55 mmol), with stirring atambient temperature for one hour. The reaction solution was diluted withwater, and extracted with ethyl acetate. The organic layer wassequentially washed with water and saturated sodium chloride solutionand dried over sodium sulfate, from which the solvents were distilledoff. The residue was purified by preparative thin layer chromatography(elution solvents:hexane:acetone=5:2), to recover the objective compound(61 mg at a yield of 28%) as a colorless needle-like crystal.

[0616] Melting Point: 172-173° C.

[0617] IR (KBr) cm⁻¹: 3432, 3267, 2967, 1664, 1509.

[0618] 1H-NMR (CDCl₃) δ: 1.04-1.12 (12H, m), 2.99 (2H, sept, J=6.9 Hz),4.15 (2H, s), 7.14 (2H, d, J=7.8 Hz), 7.28 (1H, t, J=7.8 Hz), 7.42 (1H,t, J=7.9 Hz), 7.55 (1H, d, J=7.9 Hz), 7.76 (1H, d, J=7.9 Hz), 8.36 (1H,br s).

[0619] EIMS m/z (relative intensity): 436 (M⁺, 100)

[0620] Elementary Analysis: C₂₂H₂₃F₃N₂O₂ S Required: C, 60.54; H, 5.31;N, 6.42; F, 13.06. Found: C, 60.42; H, 5.32; N, 6.39; F, 12.95.

Example 74

[0621] Production of6-(7-trifluoromethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0622] In the same manner as in Example 73 except for the use of6-bromo-N-(2,6-diisopropylphenyl)hexanamide instead of2-bromo-N-(2,6-diisopropylphenyl)acetamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

[0623] Melting Point: 130° C.

[0624] IR (KBr) cm⁻¹: 3227, 2968, 1645, 1534, 1490.

[0625] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=7.0 Hz), 1.56 (2H, m), 1.72(2H, m), 1.89 (2H, m), 2.36 (2H, m), 3.08 (2H, sept, 6.8 Hz), 3.39 (2H,t, J=7.1 Hz), 7.09 (2H, d, J=7.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.50 (1H,t, J=7.9 Hz), 7.59 (1H, d, J=7.9 Hz), 7.88 (1H, d, J=7.9 Hz), 8.69 (1H,br s).

[0626] EIMS m/z (relative intensity): 492 (M⁺), 69 (100).

[0627] Elementary Analysis: C₂₆H₃₁F₃N₂O₂S Required: C, 63.40; H, 6.34;N, 5.69. Found: C, 63.11; H, 6.43; N, 5.65.

Example 75

[0628] Production of9-(7-trifluoromethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

[0629] In the same manner as in Example 73 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of2-bromo-N-(2,6-diisopropylphenyl)acetamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

[0630] Melting Point: 82-84° C.

[0631] IR (KBr) cm⁻¹: 3436, 3244, 1648, 1506, 1332.

[0632] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.34-1.41 (6H, m),1.44-1.51 (2H, m), 1.61-1.68 (2H, m), 1.84 (2H, quint, J=7.2 Hz).2.29-2.35 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.37 (2H, t, J=7.2 Hz),7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.50 (1H, ddd, J=8.1,7.8, 0.7 Hz), 7.59 (1H, d, J=7.8 Hz), 7.88 (1H, d, J=8.1 Hz), 8.67 (1H,br s).

[0633] EIMS m/z (relative intensity): 534 (M⁺, 100)

[0634] Elementary Analysis: C₂₉H₃₇F₃N₂O₂S Required: C, 65.15; H, 6.97;N, 5.24; F, 10.66. Found: C, 65.31; H, 6.92; N, 5.29; F, 10.51.

Example 76

[0635] Production of6-(5-trifluoromethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl]hexanamide

[0636] In the same manner as in Example 11 except for the use of2-nitro-4-trifluoromethylphenol instead of3-hydroxy-6-methyl-2-nitropyridine, reaction progressed to recover2-mercapto-5-trifluoromethylbenzoxazole. The resulting product wassubjected to the same reaction in the same manner as in Example 74, torecover the objective compound as a colorless crystal.

[0637] Melting Point: 98° C.

[0638] IR (KBr) cm⁻¹: 3232, 2964, 1648 1500.

[0639] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.56 (2H, m), 1.72(2H, m), 1.88 (2H, m), 2.36 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.40(2H, t, J=7.0 Hz), 7.10 (2H, d, J=7.3 Hz), 7.20 (1H, t, J=7.3 Hz), 7.63(1H, d, J=8.6 Hz), 7.79 (1H, d, J=8.6 Hz), 7.92 (1H, s), 8.70 (1H, brs).

[0640] EIMS m/z (relative intensity): 492 (M⁺, 100).

[0641] Elementary Analysis: C₂₆H₃₁F₃N₂O₂S Required: C, 63.40; H, 6.34;N, 5.69. Found: C, 63.47; H, 6.62; N, 5.45.

Example 77

[0642] Production of6-(7-tert-butylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0643] To a solution of 2-tert-butylphenol (2.00 g, 13.3 mmol) inacetonitrile (30 ml) was dropwise added at −20° C. acetyl nitricaterecovered by mixing together acetic anhydride (1.35 g, 13.3 mmol) andfuming nitric acid (13.3 mmol) at −0° C., with stirring for 5 minutes.The reaction solution was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (60 g of silica gel;elution solvents:hexane:acetone=3:1), to recover2-tert-butyl-6-nitrophenol (600 mg at a yield of 23%) as a yellowcrystal.

[0644] In the same manner as in Example 11 except for the use of2-tert-butyl-6-nitrophenol instead of3-hydroxy-6-methyl-2-nitropyridine, reaction progressed to recover theobjective compound as a colorless crystal.

[0645] Melting Point: 141-142° C.

[0646] IR (KBr) cm⁻¹: 3247, 2961, 1654, 1505, 1117.

[0647] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.57 (2H, m), 1.72(2H, m), 1.88 (2H, m), 2.36 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.35(2H, J=7.0 Hz), 7.09 (2H, d, J=7.8 Hz), 7.18 (1H, dd, J=7.8, 1.4 Hz),7.19 (1H, t, J=7.8 Hz), 7.23 (1H, t, J=7.8 Hz), 7.42 (1H, dd, J=7.8, 1.4Hz), 8.71 (1H, br s).

[0648] EIMS m/z (relative intensity): 480 (M⁺, 100).

[0649] Elementary Analysis: C₂₆H₄₀N₂O₂S Required: C, 72.46; H, 8.39; N,5.83. Found: C, 72.19; H, 8.35; N, 5.68.

Example 78

[0650] Production of6-(4,5,6-trimethoxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0651] In the same manner as in Example 1 except for the use of4,5,6-trimethoxy-2-mercaptobenzoxazole instead of2-mercaptooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a pale yellow needle-like crystal.

[0652] Melting Point: 96-98° C. (dec.)

[0653] IR (KBr) cm⁻¹: 3428, 3231, 2964, 1648, 1485.

[0654] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.51-1.59 (2H, m),1.69-1.72 (2H, m), 1.81-1.89 (2H, m), 2.35 (2H, t, J=7.1 Hz), 3.08 (2H,sept, J=6.9 Hz), 3.30 (2H, t, J=7.1 Hz), 3.72 (3H, s), 3.82 (3H, s),4.18 (3H, S), 6.97 (1H, S), 7.09 (2H, d, J=7.8 Hz), 7.20 (1H, t, J=7.8Hz), 8.67 (1H, br s)

[0655] EIMS m/z (relative intensity): 514 (M⁺, 100).

[0656] Elementary Analysis: C₂₈H₃₈N₂O₅S Required: C, 65.34; H, 7.44; N,5.44; S, 6.23. Found: C, 65.17; H, 7.45; N, 5.44; S, 6.26.

Example 79

[0657] Production of6-(7-ethoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0658] A solution of6-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(145 mg, 0.3 mmol) and 4-dimethylaminopyridine (3.7 mg, 0.03 mmol) inethanol (30 ml) was refluxed under heating for 24 hours. Afterconcentration, the reaction solution was diluted with water, andextracted with ethyl acetate. The organic layer was sequentially washedwith 0.05 N hydrochloric acid, water and saturated sodium chloridesolution and dried over anhydrous sodium sulfate, from which thesolvents were distilled off. The residue was purified by preparativethin layer chromatography (elution solvents:hexane:acetone=5:2), torecover the objective compound (95 mg at a yield of 64%) as a colorlessneedle-like crystal.

[0659] Melting Point: 114-116° C.

[0660] IR (KBr) cm⁻¹: 3425, 3241, 2965, 1717, 1647.

[0661] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.37 (3H, t, J=7.1Hz), 1.54-1.61 (2H, m), 1.69-1.76 (2H, m), 1.86-1.93 (2H, m), 2.36 (2H,t, J=7.2 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.2 Hz), 4.40(2H, q, J=7.1 Hz), 7.09 (2H, d, J=7.8 Hz), 7.19 (1H, t, J=7.8 Hz), 7.42(1H, t. J=7.8 Hz), 7.79 (1H, dd, J=7.8, 1.2 Hz), 7.83 (1H, dd, J=7.8,1.2 Hz), 8.70 (1H, br s).

[0662] EIMS m/z (relative intensity): 496 (M⁺), 67 (100).

[0663] Elementary Analysis: C₂₈H₃₆N₂O₄S Required: C, 67.71; H, 7.31; N,5.64; S, 6.46. Found: C, 67.83; H, 7.33; N, 5.63; S, 6.52.

Example 80

[0664] Production of6-(7-methoxymethylcarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0665] To a solution of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(141 mg, 0.3 mmol) in DMF (2 ml) were added triethylamine (36 mg, 0.36mmol) and chloromethyl methyl ether (27 mg, 0.33 mmol), and theresulting mixture was stirred at ambient temperature for 50 minutes. Thereaction solution was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (10 g of silica gel;elution solvents:hexane:acetone=5:2), to recover the objective compound(119 mg at a yield of 77%) as a colorless needle-like crystal.

[0666] Melting Point: 120-122° C.

[0667] IR (KBr) cm⁻¹: 3433, 3241, 2963. 1729, 1649.

[0668] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.54-1.61 (2H,m),1.64-1.76 (2H, 1.86-1.93 (2H, m), 2.35-2.38 (2H, m), 3.08 (2H, sept,J=6.8 Hz), 3.40 (2H, t, J=7.1 Hz), 3.52 (3H, s), 5.50 (2H, s), 7.09 (2H,d, J=7.8 Hz), 7.19 (1H, t, J=7.8 Hz), 7.44 (1H, t, J=7.8 Hz), 7.83 (1H,dd, J=7.8, 1.2 Hz) 7.86 (1H, dd, J=7.8, 1.2 Hz), 8.70 (1H, br s)

[0669] EIMS m/z (relative intensity): 512 (M⁺), 67 (100).

[0670] Elementary Analysis: C₂₈H₃₆N₂O₂S Required: C, 65.60; H, 7.08; N,5.46; S, 6.25. Found: C, 65.69; H, 7.12; N, 5.42; S, 6.45.

Example 81

[0671] Production of6-(7-tert-butoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideTo a suspension of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(141 mg, 0.3 mmol) in toluene (3 ml) was dropwise addedN,N-dimethylformamide-di-tert-butyl acetal (305 mg, 1.5 mmol) withstirring at 100° C. The reaction mixture in solution was left to standand cooled and was then diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over sodium sulfate, fromwhich the solvents were distilled off. The residue was crystallized fromhexane-ether-acetone, to recover the objective compound (130 mg at ayield of 83%) as a colorless needle-like crystal.

[0672] Melting Point: 137-140° C.

[0673] IR (KBr) cm⁻¹: 3256, 2967, 1713, 1651, 1505.

[0674] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.54-1.62 (2H, m),1.60 (9H, s), 1.68-1.76 (2H, m), 1.84-1.92 (2H, m), 2.36 (2H, t, J=6.6Hz), 3.08 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.0 Hz), 7.09 (2H, d,J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.39 (1H, t, J=7.8 Hz), 7.73 (1H, dd,J=7.8, 1.2 Hz), 7.79 (1H, dd, J=7.8, 1.2 Hz), 8.70 (1H, br s).

[0675] EIMS m/z (relative intensity): 524 (M⁺), 468 (100).

[0676] Elementary Analysis: C₃₀H₄₀N₂O₄S Required: C, 68.67; H, 7.68; N,5.34; S, 6.11. Found: C, 68.70; H, 7.54; N, 5.33; S, 6.23.

Example 82

[0677] Production of6-(7-tert-butoxycarbonylmethyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0678] In the same manner as in Example 59 except for the use oftert-butyl glycolic acid instead of N,N-dimethyl ethanolamine, reactionprogressed to recover the objective compound as a colorless needle-likecrystal.

[0679] Melting Point: 77-79° C.

[0680] IR (KBr) cm⁻¹: 3244, 2964, 1755, 1735, 1647.

[0681] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.45 (9H, s),1.52-1.62 (2H, m), 1.64-1.74 (2H, m), 1.84-1.92 (2H, m), 2.36 (2H, t,J=6.8 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.40 (2H, t, J=7.0 Hz), 4.81 (2H,s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.45 (1H, t, J=7.8Hz), 7.84 (1H, dd, J=7.8, 1.2 Hz), 7.87 (1H, dd, J=7.8, 1.2 Hz), 8.70(1H, br s).

[0682] EIMS m/z (relative intensity): 582 (M⁺), 525 (100).

[0683] Elementary Analysis: C₃₂H₄₂N₂O₆S Required: C, 65.95; H, 7.26; N,4.81; S, 5.50. Found: C, 66.09; H, 7.29; N, 4.78; S, 5.53.

Example 83

[0684] Production of6-[7-(3-methyloxethan-3-ylmethyloxycarbonyl)benzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0685] In the same manner as in Example 59 except for the use of3-methyl-3-oxethane methanol instead of N,N-dimethyl ethanolamine,reaction progressed to recover the objective compound (340 mg at a yieldof 60%) as a colorless needle-like crystal.

[0686] Melting Point: 145-147° C.

[0687] IR (KBr) cm⁻¹: 3425, 3254, 2965, 1722, 1647.

[0688] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.40 (3H, s),1.52-1.62 (2H, m), 1.64-1.76 (2H, m), 1.84-1.92 (2H, m), 2.36 (2H, t,J=6.9 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.0 Hz), 4.32 (2H,d, J=5.9 Hz), 4.47 (2H, s), 4.54 (2H, J=5.9 Hz), 7.09 (2H, d, J=7.6 Hz),7.20 (1H, t, J=7.6 Hz), 7.44 (1H, t, J=8.0 Hz), 7.83 (1H, dd, J=8.0, 1.2Hz), 7.85 (1H, dd, J=8.0, 1.2 Hz), 8.70 (1H, br s).

[0689] EIMS m/z (relative intensity): 552 (M⁺), 230 (100).

[0690] Elementary Analysis: C₃₁H₄₀N₂O₅S Required: C, 69.50; H, 7.34; N,6.00; S, 6.87. Found: C, 69.47; H, 7.33; N, 6.08; S, 6.95.

Example 84

[0691] Production of6-[7-(4,4-dimethyloxazolin-2-yl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0692]6-(7-Methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(241 mg, 0.5 mmol) was added to 2-amino-2-methyl-1-propanol (3 ml), withstirring at 100° C. for 6 hours. The reaction solution was diluted withwater, and extracted with ethyl acetate. The organic layer wassequentially washed with diluted hydrochloric acid, water, an aqueoussodium hydrogen carbonate solution and saturated sodium chloridesolution and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (20 g of silica gel; elutionsolvents:hexane:acetone=5:2), to recover6-[7-[N-(1-hydroxy-2-methyl-2propyl)carbamoyl]benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide(140 mg at a yield of 52%) as a pale yellow needle-like crystal.

[0693] The amide (108 mg, 0.2 mmol) was added to phosphorus oxychloride(1 ml) under cooling in ice bath, and the resulting mixture was stirredat the temperature for 10 minutes. The reaction mixture was poured intoice bath water, and extracted with ethyl acetate. The organic layer wassequentially washed with water and saturated sodium chloride solutionand dried over anhydrous sodium sulfate, from which the solvents weredistilled off. The resulting residue was purified by preparative thinlayer chromatography (elution solvents; hexane:acetone=5:3), to recoverthe objective compound (67 mg at a yield of 64%) as a colorlessneedle-like crystal.

[0694] Melting Point: 127-129° C.

[0695] IR (KBr) cm⁻¹: 3430, 3261, 2964, 1652, 1505.

[0696] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.33 (6H, s),1.52-1.62 (2H, m), 1.66-1.76 (2H, m), 1.86-1.94 (2H, m), 2.36 (2H, t,J=6.8 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.37 (2H, t, J=7.2 Hz), 4.13 (2H,s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.37 (1H, t, J=7.9Hz), 7.71 (1H, dd, J=7.9, 1.2 Hz), 7.72 (1H, dd, J=7.9, 1.2 Hz), 8.70(1H, br s).

[0697] EIMS m/z (relative intensity): 521 (M⁺), 262 (100).

[0698] Elementary Analysis: C₃₀H₃₉N₃O₃S Required: C, 69.07; H, 7.53; N,8.05; S, 6.15. Found: C, 69.05; H, 7.56; N, 7.95; S, 6.24.

Example 85

[0699] Production of6-[7-([1,3]dioxolan-2-yl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0700] To a solution of6-(7-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(440 mg, 1.0 mmol) in methylene chloride (10 ml) were sequentially addedmolecular sieves 4A (powder, 2 g) and pyridinium dichromate (1.1 g, 2.9mmol), and the resulting mixture was stirred at ambient temperature for30 minutes. The reaction mixture was diluted with ether and filtered offthrough celite; and the filtrate was concentrated. The residue waspurified by silica gel column chromatography (20 g of silica gel;elution solvents; hexane:acetone=5:3), to recover6-(7-formylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (330mg at a yield of 75%) as a colorless needle-like crystal.

[0701] To a solution of the aldehyde (136 mg, 0.3 mmol) in toluene (5ml) were sequentially added ethylene glycol (130 mg, 2.1 mmol),trimethyl o-formate (133 mg, 0.9 mmol) and p-toluenesulfonicacid-monohydrate (10 mg, 0.05 mmol), with stirring at 50° C. for 4 hoursand additionally at 100° C. for 4 hours. The resulting reaction solutionwas diluted with water, and extracted with ethyl acetate. The organiclayer was washed sequentially with an aqueous saturated sodium hydrogencarbonate solution, water and saturated sodium chloride solution anddried over anhydrous sodium sulfate, from which the solvents weredistilled off. The residue was purified by preparative thin layerchromatography (elution solvents:hexane:acetone=5:2), to recover a solidmatter; then, the solid matter was crystallized from hexane-ether, torecover the objective compound (76 mg at a yield of 51%) as a colorlessneedle-like crystal.

[0702] Melting Point: 105-107° C.

[0703] IR (KBr) cm⁻¹: 3432, 3221, 2963, 1643, 1537.

[0704] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.61 (2H, m),1.67-1.76 (2H, m), 1.82-1.91 (2H, m), 2.36 (2H, t, J=6.9 Hz), 3.08 (2H,sept, J=6.8 Hz), 3.36 (2H, t, J=7.2 Hz), 3.98-4.13 (4H, m), 6.11 (1H,s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.30 (1H, t, J=7.6Hz), 7.34 (1H, dd, J=7.6, 1.6 Hz), 7.59 (1H, dd, J=7.6, 1.6 Hz), 8.70(1H, br s).

[0705] EIMS m/z (relative intensity): 496 (M⁺,100).

[0706] Elementary Analysis: C₂₈H₃₆N₂O₄S Required: C, 67.71; H, 7.31; N,5.64; S, 6.46. Found: C, 67.88; H, 7.31; N, 5.62; S, 6.61.

Example 86

[0707] Production of6-[7-(4R,5R)-4,5-dimethyl[1,3]dioxolan-2-yl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0708] In the same manner as in Example 85 except for the use of(2R,3R)-2,3-butanediol instead of ethylene glycol, reaction progressedto recover the objective compound (101 mg at a yield of 64%) as acolorless needle-like crystal.

[0709] Melting Point: 115-117° C.

[0710] IR (KBr) cm⁻¹: 3424, 3236, 2969, 1646, 1499.

[0711] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.27-1.33 (6H, m),1.52-1.62 (2H, m), 1.66-1.76 (2H, m), 1.86-1.94 (2H, m), 2.36 (2H, t,J=6.2 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.36 (2H, t, J=7.2 Hz), 3.79-3.87(2H, m), 6.21 (1H, s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz),7.30 (1H, t, J=7.6 Hz), 7.35 (1H, dd, J=7.6, 1.4 Hz), 7.58 (1H, dd,J=7.6, 1.4 Hz), 8.70 (1H, br s).

[0712] EIMS m/z (relative intensity): 524 (M⁺), 452 (100).

[0713] Elementary Analysis: C₃₀H₄₀N₂O₄S Required: C, 68.67; H, 7.68; N,5.34; S, 6.11. Found: C, 68.87; H, 7.68; N, 5.28; S, 6.24.

Example 87

[0714] Production of6-(7-acetylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0715] Potassium o-ethyl dithiocarbonate (241 mg, 1.5 mmol) was added toa solution of 3-amino-2-hydroxyacetophenone (113 mg, 0.75 mmol) inethanol (10 ml), at reflux under heating for 16 hours, from which thesolvent was distilled off. The residue was dissolved in water, followedby addition of 2 N hydrochloric acid to adjust the resulting solution topH 3 to 4. The deposited crystal was filtered and recovered; then, thecrystal was washed with water and dried with heating under reducedpressure, to recover 7-acetyl-2-mercaptobenzoxazole (134 mg at a yieldof 92%) as a brown solid.

[0716] In the same manner as in Example 1 except for the use of theoxazole herein recovered instead of 2-mercaptooxazolo[4,5-b]pyridine,reaction progressed to recover the objective compound as a colorlessneedle-like crystal.

[0717] Melting Point: 156-158° C.

[0718] IR (KBr) cm⁻¹: 3437, 3218, 2958, 1682, 1651.

[0719] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.62 (2H, m),1.66-1.76 (2H, m), 1.86-1.94 (2H, m), 2.37 (2H, t, J=6.9 Hz), 2.69 (3H,s), 3.08 (2H, sept, J=6.8 Hz), 3.40 (2H, t, J=7.0 Hz), 7.09 (2H, d,J=7.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.42 (1H, t, J=7.8 Hz), 7.75 (1H, dd,J=7.8, 1.1 Hz), 7.82 (1H, dd, J=7.8, 1.1 Hz), 8.71 (1H, br s).

[0720] EIMS m/z (relative intensity): 466 (M⁺), 177 (100).

[0721] Elementary Analysis: C₂₇H₃₄N₂O₃S Required: C, 69.50; H, 7.34; N,6.00; S, 6.87. Found: C, 69.47; H, 7.33; N, 6.08; S, 6.95.

Example 88

[0722] Production of6-[7-(pyrazol-3-yl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamideTo a solution of6-(7-acetylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (155mg, 0.33 mmol) in DMF (3 ml) was addedN,N-dimethylformamide-dimethylacetal (191 mg, 1.6 mmol), with stirringat 50° C. for 4 hours and additionally at 100° C. for 15 hours. Thereaction solution was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over sodium sulfate, fromwhich the solvent was distilled off. The residue was purified bypreparative thin layer chromatography (elutionsolvents:hexane:acetone=5:3), to recover6-[7-(3-dimethylaminoacryloyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide(146 mg at a yield of 85%) as a pale yellow needle-like crystal.

[0723] To a solution of the enamine (104 mg, 0.2 mmol) in methanol (3ml) were added acetic acid (60 mg, 1.0 mmol) and hydrazine.monohydrate(50 g, 1.0 mmol), with stirring at ambient temperature for 2 hours. Thereaction solution was concentrated and then diluted with water, andextracted with ethyl acetate. The organic layer was sequentially washedwith water and saturated sodium chloride solution and dried over sodiumsulfate, from which the solvents were distilled off. The residue waspurified by preparative thin layer chromatography (elutionsolvents:hexane:acetone=1:1), to recover the objective compound (75 mgat a yield of 76%) as a colorless needle-like crystal.

[0724] Melting Point: 174-176° C.

[0725] IR (KBr) cm⁻¹: 3236, 2964, 1647, 1530, 1493.

[0726] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.62 (2H, m),1.66-1.76 (2H, m), 1.86-1.94 (2H, m), 2.37 (2H, t, J=6.9 Hz), 3.08 (2H,sept, J=6.8 Hz), 3.40 (2H, t, J=6.7 Hz), 6.81 (1H, m), 7.09 (2H, d,J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.30 (1H, t, J=7.6 Hz), 7.34 (1H, m),7.52 (1H, m), 7.75-7.80 (2H, m), 8.70 (1H, br s), 12.79 (1H, br s).

[0727] EIMS m/z (relative intensity): 490 (M⁺), 176 (100).

[0728] Elementary Analysis: C₂₈H₃₆N₂O₄S Required: C, 68.54; H, 6.98; N,11.42; S, 6.53. Found: C, 68.65; H, 7.05; N, 11.30; S, 6.57.

Example 89

[0729] Production of6-[6,7-bis(methoxycarbonyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

[0730] In the same manner as in Example 1 except for the use of 6,7-bis(methoxycarbonyl)-2-mercaptobenzoxazole instead of2-mercaptooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

[0731] Melting Point: 159-161° C.

[0732] IR (KBr) cm⁻¹: 3425, 3257, 1744, 1721, 1647.

[0733] 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.60 (2H, m),1.68-1.75 (2H, m), 1.85-1.92 (2H, m), 2.36 (2H, t, J=7.1 Hz), 3.08 (2H,sept, J=6.8 Hz), 3.40 (2H, t, J=7.1 Hz), 3.85 (3H, s), 3.91 (3H, s),7.09 (2H, d, J=7.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.77 (1H, d, J=8.3 Hz),7.81 (1H, d, J=8.3 Hz), 8.67 (1H, br s)

[0734] EIMS m/z (relative intensity): 540 (M⁺), 162 (100).

[0735] Elementary Analysis: C₂₉H₃₆N₂O₆S Required: C, 64.42; H, 6.71; N,5.18. Found: C, 64.56; H, 6.69; N, 5.26.

Example 90

[0736] Production of6-(oxazolo[4,5-g]phthalid-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0737] To a solution of 2,3-bis(methoxycarbonyl)phenol (4.6 g, 20 mmol)in acetonitrile (100 ml) was dropwise added at 0° C. acetyl nitricateacid recovered by mixing together acetic anhydride (6.0 g, 60 mmol) andfuming nitric acid (3.6 g, 60 mmol) at 0° C., with stirring for 40minutes. The reaction solution was diluted with water, and extractedwith ethyl acetate. The organic layer was sequentially washed with waterand saturated sodium chloride solution and dried over anhydrousmagnesium sulfate, from which the solvents were distilled off. Theresidue was purified by silica gel column chromatography (100 g ofsilica gel; elution solvents:hexane:acetone=5:2), to preferentiallyrecover 2,3-bis(methoxycarbonyl)-6-nitrophenol (1.34 g at a yield of32%) as a yellow crystal from ether.

[0738] To a solution of the diester (1.27 g, 5 mmol) in THF (4 ml) andt-BuOH (4 ml) in mixture was added an aqueous solution of lithiumhydroxide (420 mg, 10 mmol) at 0° C., with stirring at ambienttemperature for 24 hours. The reaction solution was adjusted to acidityby using 2 N hydrochloric acid, and extracted with ethyl acetate. Theorganic layer was sequentially washed with water and saturated sodiumchloride solution and dried over anhydrous magnesium sulfate, from whichthe solvents were distilled off, to recover3-hydroxy-2-methoxycarbonyl-4-nitrobenzoic acid (728 mg at a yield of60%) as a yellow crystal.

[0739] To a THF solution of the benzoic acid (650 mg, 2.7 mmol) wasdropwise added borane (1.0 M THF solution, 8.1 ml, 8.1 mmol) at 0° C.under argon atmosphere, with stirring at ambient temperature for 24hours. The reaction solution was diluted with water and adjusted toacidity by using 2 N hydrochloric acid, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (20 g of silica gel;elution solvents:chloroform:methanol=20:1), to recover6-nitro-7-hydroxyphthalide (290 mg at a yield of 61%) as a yellowcrystal.

[0740] To a solution of the nitrophthalide (290 mg, 1.5 mmol) in ethanol(20 ml) was added a catalyst 10% palladium-carbon (300 mg), and theresulting mixture was stirred at ambient temperature under hydrogenatmosphere for 3 hours. The reaction solution was subjected tofiltration through celite. Potassium o-Ethyl dithiocarbonate (280 mg,1.7 mmol) was added to the resulting filtrate, with stirring underheating for 16 hours. After the solution was left to stand and cooled,the solvents were distilled off under reduced pressure. The residue wasdiluted with 2 N hydrochloric acid to adjust the resulting solution toacidity, and extracted with ethyl acetate. The organic layer wassequentially washed with water and saturated sodium chloride solution,and was then dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (15 g of silica gel; elutionsolvents:chloroform:methanol=20:1). The resulting solid was crystallizedfrom acetone and hexane, to recover 2-mercaptooxazolo[4,5-g]phthalide(225 mg at a yield of 80%) as a colorless needle-like crystal.

[0741] In the same manner as in Example 1 except for the use of thephthalide herein recovered instead of 2-mercaptooxazolo[4,5-b]pyridine,reaction progressed to recover the objective compound as a colorlessneedle-like crystal.

[0742] Melting Point: 161-162° C.

[0743] IR (KBr) cm⁻¹: 3243, 2959, 1768, 1647, 1263.

[0744] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.56 (2H, m), 1.72(2H, m), 1.89 (2H, m), 2.47 (2H, m), 3.08 (2H, sept, J=7.0 Hz), 3.40(2H, t, J=7.0 Hz), 5.57 (2H, s), 7.09 (2H, d, J=7.4 Hz), 7.18 (1H, t,J=7.4 Hz), 7.78 (2H, m), 8.71 (1H, br, s).

[0745] EIMS m/z (relative intensity): 480 (M⁺), 162 (100).

[0746] Elementary Analysis: C₂₇H₃₂N₂O₄S Required: C, 67.47; H, 6.71; N,5.83; Found: C, 67.37; H, 6.75; N, 5.78;

Example 91

[0747] Production of6-[6-hydroxy-7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

[0748] In the same manner as in Example 77 except for the use of ethyl2,6-dihydroxybenzoate instead of 2-tert-butylphenol, reaction progressedto recover the objective compound as a colorless crystal.

[0749] Melting Point: 155-156° C.

[0750] IR (KBr) cm⁻¹: 3228, 2966, 1677, 1645, 1513.

[0751] 1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.55 (2H, m), 1.71(2H, m), 1.86 (2H, m), 2.35 (2H, m), 3.08 (2H, sept, J=7.0 Hz), 3.32(2H, t, J=7.0 Hz), 3.97 (3H, s), 6.92 (1H, d, J=8.7 Hz), 7.09 (2H, d,J=7.4 Hz), 7.20 (1H, t, J=7.4 Hz), 7.67 (1H, d, J=8.7 Hz), 8.69 (1H, br,s).

[0752] EIMS m/z (relative intensity):

[0753] Elementary Analysis: C₂₇H₃₄N₂O₅S.1/2H₂O Required: C, 63.88; H,6.95; N, 5.52; Found: C, 63.93; H, 6.87; N, 5.37;

Example 92

[0754] Production of6-[6,7-dihydro-7,7-dimethyloxazolo[4,5-g]benzofuran]-2-ylthio-N-(2,6-diisopropylphenyl)hexanamide

[0755] In the same manner as in Example 77 except for the use of2,3-dihydro-2,2-dimethyl-7-benzofuranol instead of 2-tert-butylphenol,reaction progressed to recover the objective compound as a colorlesscrystal.

[0756] Melting Point: 136-137° C.

[0757] IR (KBr) cm¹: 3417, 3249, 2984, 1648, 1509 1H-NMR (d₆-DMSO) δ:1.12 (12H, d, J=6.8 Hz), 1.49 (6H, s), 1.51-1.61 (2H, m), 1.66-1.76 (2H,m), 1.80-1.88 (2H, m), 2.36 (2H, t, J=6.6 Hz), 3.08 (2H, sept, J=6.8Hz), 3.12 (2H, s), 3.33 (2H, t, J=7.1 Hz), 7.02 (2H, d, J=7.8 Hz), 7.09(2H, d, J=7.8 Hz), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 8.70(1H, br s)

[0758] EIMS m/z (relative intensity):494(M⁺), 176(100)

[0759] Elementary Analysis: C₂₉H₃₈N₂O₃S Required: C, 70.41; H, 7.74; N,5.66; Found: C, 70.36; H, 7.64; N, 5.75;

[0760] Industrial Applicability

[0761] As has been described above, the novel anilide compound of theinvention is useful in the form of pharmaceutical composition,specifically as acyl coenzyme A cholesterol acyltransferase (ACAT)inhibitor.

1. A compound represented by the general formula I, a salt thereof or asolvated compound thereof:

represents a divalent residue of benzene with a substituent(s),heterocycle-condensed benzene which may or may not have a substituent,pyridine which may or may not have a substituent, cyclohexane ornaphthalene

Ar represents an aryl group which may or may not have a substituent; Xrepresents —NH—, oxygen atom or sulfur atom; Y represents —NR₄—, oxygenatom, sulfur atom, sulfoxide or sulfone; Z represents single bond or—NR₅—; R₄ represents hydrogen atom, a lower alkyl group, an aryl groupor a silylated lower alkyl group which may or may not have asubstituent; R₅ represents hydrogen atom, a lower alkyl group, an arylgroup or a silylated lower alkyl group which may or may not have asubstituent; and n represents an integer of 0 to
 15. 2. A compoundrepresented by the following formula II, a salt thereof or a solvatedproduct thereof:

represents a divalent residue of benzene with a substituent(s),heterocycle-condensed benzene which may or may not have a substituent,pyridine which may or may not have a substituent, cyclohexane ornaphthalene

X represents —NH—, oxygen atom or sulfur atom; Y represents —NR₄—,oxygen atom, sulfur atom, sulfoxide or sulfone; Z represents single bondor —NR₅—; R₁, R₂ and R₃ may be the same or different and representhydrogen atom, a lower alkyl group, a lower alkoxyl group, halogen atom,hydroxyl group, phosphate group, sulfonamide group, or amino group whichmay or may not have a substituent; otherwise, any combination of two ofR₁, R₂ and R₃ represents an alkylene dioxy group; R₄ represents hydrogenatom, a lower alkyl group, an aryl group or a silylated lower alkylgroup which may or may not have a substituent; R₅ represents hydrogenatom, a lower alkyl group, an aryl group or a silylated lower alkylgroup which may or may not have a substituent; and n represents aninteger of 0 to
 15. 3. A compound represented by the following formulaIII, a salt thereof or a solvated product thereof:

wherein X represents —NH—, oxygen atom or sulfur atom; Y represents—NR₄—, oxygen atom, sulfur atom, sulfoxide or sulfone; Z representssingle bond or —NR₅—; R₁, R₂ and R₃ may be the same or different andrepresent hydrogen atom, a lower alkyl group, a lower alkoxyl group,halogen atom, hydroxyl group, phosphate group, sulfonamide group, oramino group which may or may not have a substituent; otherwise, anycombination of two of R₁, R₂ and R₃ represents alkylene dioxy group; R₄represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent; R₅represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent; R₆,R₇ and R₈ may be the same or different and represent hydrogen atom, alower alkyl group which may or may not have a substituent, a loweralkoxyl group which may or may not have a substituent, halogen atom,hydroxyl group, carboxyl group, an alkoxycarbonyl group which may or maynot have a substituent, an alkylcarbonyloxy group which may or may nothave a substituent, an alkylcarbonyl group which may or may not have asubstituent, carbamoyl group which may or may not have a substituent, ahydroxyalkyl group, phosphate group, cyano group, nitro group,sulfonamide group, amino group which may or may not have a substituent,an aminoalkyl group which may or may not have a substituent, or aheterocyclic residue; otherwise, any combination of two of R₆, R₇ and R₈represents an alkylene dioxy group, provided that R₆, R₇ and R₈ neversimultaneously represent hydrogen atom; and n represents an integer of 0to
 15. 4. A compound represented by the following general formula IV, asalt thereof or a solvated product thereof:

X represents —NH—, oxygen atom or sulfur atom; Y represents —NR₄—,oxygen atom, sulfur atom, sulfoxide or sulfone; Z represents single bondor —NR₅—; R₁, R₂ and R₃ may be the same or different and representhydrogen atom, a lower alkyl group, a lower alkoxyl group, halogen atom,hydroxyl group, phosphate group, sulfonamide group, or amino group whichmay or may not have a substituent; otherwise, any combination of two ofR₁, R₂ and R₃ represents an alkylene dioxy group; R₄ represents hydrogenatom, a lower alkyl group, an aryl group or a silylated lower alkylgroup which may or may not have a substituent; R₅ represents hydrogenatom, a lower alkyl group, an aryl group or a silylated lower alkylgroup which may or may not have a substituent; R₉, R₁₀, R₉′, R₁₀′, R₉″,R₁₀″, R₉′″, and R₁₀′″ may be the same or different and representhydrogen atom, a lower alkyl group which may or may not have asubstituent, a lower alkoxyl group which may or may not have asubstituent, halogen atom, hydroxyl group, carboxyl group, analkoxycarbonyl group which may or may not have a substituent, analkylcarbonyloxy group which may or may not have a substituent, analkylcarbonyl group which may or may not have a substituent, carbamoylgroup which may or may not have a substituent, a hydroxyalkyl group,phosphate group, sulfonamide group, amino group which may or may nothave a substituent, an aminoalkyl group which may or may not have asubstituent, or a heterocyclic residue; otherwise, any combination oftwo thereof represents an alkylene dioxy group; and n represents aninteger of 0 to
 15. 5. A pharmaceutical composition comprising acompound, a salt thereof or a solvated compound thereof according to anyone of claims 1 to 4, and a pharmaceutically acceptable carrier.
 6. Apharmaceutical composition according to claim 5, which is an ACATinhibitor, an intra-cellular cholesterol transfer inhibitory agent, ablood cholesterol-reducing agent or a macrophage foaming-suppressingagent.
 7. A pharmaceutical composition according to claim 5, which is aprophylactic and therapeutic agent of hyperlipidemia, arteriosclerosis,cerebrovascular diseases, ischemic cardiac diseases, ischemic intestinaldiseases or aortic aneurysm.
 8. A method for therapeutically treatingdiseases with the etiology of ACAT, intra-cellular cholesterol transfer,blood cholesterol or macrophage foaming, comprising administering atherapeutically effective dose of a compound, a salt thereof or asolvated compound thereof according to any one of claims 1 to
 4. 9. Amethod for therapeutically treating hyperlipidemia, arteriosclerosis,cerebrovascular diseases, ischemic cardiac diseases, ischemic intestinaldiseases or aortic aneurysm, comprising administering a therapeuticallyeffective dose of a compound, a salt thereof or a solvated compoundthereof according to any one of claims 1 to
 4. 10. The use of acompound, a salt thereof or a solvated compound thereof according to anyone of claims 1 to 4, for producing an ACAT inhibitor, an intra-cellularcholesterol transfer inhibitory agent, a blood cholesterol-reducingagent or a macrophage foaming-suppressing agent.
 11. The use of acompound, a salt thereof or a solvated compound thereof according to anyone of claims 1 to 4, for therapeutically treating hyperlipidemia,arteriosclerosis, cerebrovascular diseases, ischemic cardiac diseases,ischemic intestinal diseases or aortic aneurysm.